PPAR agonist compounds, preparation and uses

ABSTRACT

The present invention relates to novel PPAR agonist compounds as well as pharmaceutical compositions containing them. The compounds according to the invention are of quite particular therapeutic interest, notably for treating diabetes and/or dyslipidemias, as well as for preventing cardiovascular pathologies.

This application is the U.S. national phase of International ApplicationNo. PCT/FR2009/050980 filed 26 May 2009, which designated the U.S. andclaims priority to France Application No. 0853415 filed 26 May 2008, theentire contents of each of which are hereby incorporated by reference.

The present invention relates to compounds of therapeutic interest,intended notably for treating diabetes and/or dyslipidemias. Theinvention also relates to pharmaceutical compositions comprising saidcompounds.

Diabetes and dyslipidemias (high plasma levels of LDL cholesterol and oftriglycerides, low HDL cholesterol, etc.) are included among the clearlyidentified cardiovascular risk factors that predispose an individual todevelop a cardiovascular pathology (The Atlas of Heart Disease andStroke, edited by Mackay J and Mensah M, published by World HealthOrganization, 2004). These risk factors are additional to the riskfactors associated with lifestyle such as smoking, physical inactivityand an unbalanced diet. There is a synergistic effect between thesevarious factors: the simultaneous presence of several of them leads to adramatic worsening of cardiovascular risk and it is then best to talk ofglobal risk for cardiovascular diseases. The prevalence of dyslipidemiasreached 43.6% of the population in 2004 in the main developed countries.The prevalence of diabetes, currently showing a marked increase, willbecome increasingly significant in the epidemiology of cardiovasculardiseases. It is estimated at 7.6% of the population for 2010 (Fox-TuckerJ, The Cardiovascular Market Outlook to 2010, Business Insights Reports,2005).

According to the International Atherosclerosis Society, cardiovasculardiseases represent the primary cause of mortality in the industrializedcountries and are becoming more and more common in the developingcountries. These diseases are notably coronary diseases, cerebralischemia and peripheral arterial diseases. These data justify theadoption of energetic measures for significantly reducing cardiovascularmorbidity and mortality. Equally, the need to find effective treatments,capable of acting on the risk factors of cardiovascular diseases and ontheir consequences, is now of global urgency, also in view of recentdisappointing results with candidate drugs (Krause B, 2008).

Among the various nuclear receptors that can be therapeutic targets(Hansen M K and Connolly T M, 2008), the involvement of PeroxisomeProliferator-Activated Receptors (PPARs) in pathologies of this type isnow very well established (Blaschke F et al., 2006; Gilde A J et al.,2006; Gervois P et al., 2007). The PPAR family comprises three isoforms,designated α, γ and δ (also called β), each encoded by a different gene.These receptors, which form part of the superfamily of nuclear receptorsand of transcription factors, have a major role in regulation of lipidand carbohydrate metabolism.

PPARα controls lipid metabolism (hepatic and muscular) and glucosehomeostasis, and influences intracellular metabolism of lipids andsugars by direct control of transcription of the genes coding forproteins involved in lipid homeostasis. PPARα also exertsanti-inflammatory and antiproliferative effects and prevents theproatherogenic effects of accumulation of cholesterol in macrophages bystimulating the outflow of cholesterol (Lefebvre P et al., 2006). PPARγis a key regulator of adipogenesis. It is also involved in the lipidmetabolism of mature adipocytes, in glucose homeostasis, in insulinresistance, in inflammation, in accumulation of cholesterol at themacrophage level and in cellular proliferation (Lehrke M and Lazar M A,2005). PPARγ consequently plays a role in the pathogenesis of obesity,insulin resistance and diabetes. PPARδ is involved in controlling lipidand carbohydrate metabolism, in the energy balance, inneurodegeneration, in obesity, in the formation of foam cells and ininflammation (Gross B et al., 2005).

These multiple properties make PPARs therapeutic targets of interest forthe treatment of diabetes and dyslipidemias, and for the prevention ofcardiovascular diseases. Ligands of PPARs are already known, some aremarketed and prescribed in the treatment of some of the pathologiesmentioned above, and their toxicology has been investigated (Peraza M etal., 2006). We may mention activators of PPARα, such as fibrates(fenofibrate, bezafibrate, ciprofibrate, gemfibrozil), which are used inclinical practice for treating certain dyslipidemias by increasingplasma levels of HDL (High Density Lipoprotein) and by loweringtriglycerides (Hourton D et al. 2001). Moreover, thiazolidinediones(rosiglitazone and pioglitazone), ligands of PPARγ, are used in thetreatment of type 2 diabetes. Ligands of PPARδ are also known (such asL-165041, GW501516 and KD3010). Among the documents of the prior artmentioning similar compounds, patent applications WO 03/084916, WO08/152333, WO 05/041959, WO 08/066356, EP 1266888, and US 2005096336describe PPAR receptor agonists.

The invention proposes novel compounds that are agonists of PPARs (PPARαand/or PPARγ and/or PPARδ), and in particular are suitable for thetherapeutic and/or prophylactic treatment of diabetes, dyslipidemias,insulin resistance, pathologies associated with metabolic syndrome,atherosclerosis, obesity, hypertension and/or inflammatory diseases.These PPAR agonist compounds can also be particularly effective forreducing cardiovascular risk, and for preventing cardiovasculardiseases, notably those associated with disorders of lipid and/orcarbohydrate metabolism.

These and other aims are achieved by compounds of the following generalformula (I):

in which,

-   G represents:    -   a radical —OR_(a), —SR_(a); or    -   a radical —NR_(a)R_(b);    -   R_(a) being selected from an alkyl radical with 1 to 6 carbon        atoms or alkenyl radical with 2 to 6 carbon atoms, a ring with 3        to 14 atoms, a phenyl radical, a phenylalkyl radical with the        alkyl moiety having 1 to 3 carbon atoms;    -   R_(b) being selected from a hydrogen atom, an alkyl radical with        1 to 6 carbon atoms or alkenyl radical with 2 to 6 carbon atoms,        a ring with 3 to 14 atoms, a phenyl radical, or a phenylalkyl        radical with the alkyl moiety having 1 to 3 carbon atoms;    -   and R_(a) and R_(b) can form, together and with the nitrogen        atom to which they are bound, a heterocycle with 3 to 8 atoms;        R₁ and R₂, which may be identical or different, represent a        hydrogen atom or an alkyl radical with 1 to 6 carbon atoms or        alkenyl radical with 2 to 6 carbon atoms;        and R₁ and R₂ can form, together and with the carbon atom to        which they are bound, a carbocycle with 3 to 6 carbon atoms;-   Y₁ represents:    -   an oxygen, sulfur or selenium atom, or    -   a group —NR—, in which R has the same definition as R_(b);-   Y₂ represents:    -   an oxygen, sulfur or selenium atom, or    -   a radical —CR₅R₆—; with R₅ and R₆, which may be identical or        different, selected from a hydrogen atom or halogen atom, an        alkyl radical with 1 to 6 carbon atoms or an alkenyl or alkynyl        radical with 2 to 6 carbon atoms, a ring with 3 to 6 atoms, a        phenylalkyl radical with the alkyl moiety having 1 to 3 carbon        atoms,        and R₅ and R₆ can form, together and with the carbon atom to        which they are bound, a ring with 3 to 6 atoms;        X₁, X₂, X₃ represent independently a hydrogen atom or halogen        atom, an alkyl radical with 1 to 6 carbon atoms or alkenyl        radical with 2 to 6 carbon atoms, a group —OR′_(a), —SR′_(a),        —NR′_(a)R′_(b), a ring with 5 to 14 atoms, or a phenylalkyl        radical with the alkyl moiety having 1 to 3 carbon atoms,        with at least one of the groups X₁, X₂ and X₃ different from a        hydrogen atom and from a halogen atom,        and X₁, X₂ and X₃ can form two at a time, with the two carbon        atoms to which they are bound, a carbocycle with 6 carbon atoms;        R′_(a) and R′_(b), which may be identical or different, having        the same definitions as R_(a) and R_(b);        X₄ and X₅ represent independently a hydrogen atom or halogen        atom, an alkyl radical with 1 to 6 carbon atoms or alkenyl        radical with 2 to 6 carbon atoms, a group —OR″_(a), —SR″_(a) or        —NR″_(a)R″_(b), a ring with 3 to 14 atoms, a phenyl radical, or        a phenylalkyl radical with the alkyl moiety having 1 to 3 carbon        atoms;        and X₄ and X₅ can be bound to two adjacent carbon atoms and        form, together and with said adjacent carbon atoms, a ring with        6 atoms;        R−_(a) and R″_(b), which may be identical or different, having        the same definitions as R_(a) and R_(b);        R₃ and R₄, which may be identical or different, represent a        hydrogen atom or halogen atom, an alkyl radical with 1 to 6        carbon atoms or alkenyl radical with 2 to 6 carbon atoms, a ring        with 3 to 14 atoms, a phenyl radical, or a phenylalkyl radical        with the alkyl moiety having 1 to 3 carbon atoms;        R₃ and R₄ can form, together and with the carbon atom to which        they are bound, a ring with 3 to 6 atoms;        W represents:    -   a carboxyl radical —COON; or    -   a function derived from the carboxylic acid function, selected        from —COOR′″_(a), —COSR′″_(a), —CONR′″_(a)R′″_(b),        —CSNR′″_(a)R′″_(b), —CONH₂; or    -   a bioisosteric group of the carboxyl radical, selected from:    -   an acylsulfonamide radical (—CONHSO₂R′″_(a));    -   a hydrazide radical (—CONHNR′″_(a)R′″_(b));    -   a radical selected from the thiazolidinedione, oxazolidinedione,        tetrazole, oxadiazolone, triazolone, triazole, 3-alkyltriazole,        or imidazolidinedione rings;        R′″_(a) and R′″_(b), which may be identical or different, having        the same definitions as R_(a) and R_(b).

Within the scope of the present invention, the following definitions areapplicable:

-   Alkyl, alkenyl or alkynyl radicals with n carbon atoms mean,    according to the invention, linear, saturated or unsaturated,    branched or unbranched hydrocarbon radicals, formed with a total of    n carbon atoms (carbon atoms of the main chain and carbon atoms of    the branchings), comprising from 1 to 12 carbon atoms and, more    particularly, from 1 to 6 carbon atoms. This definition also    includes alkyl, alkenyl or alkynyl radicals substituted with one or    more halogen atoms. The alkyl radicals with 1 to 6 carbon atoms are    preferably the methyl, ethyl, n-propyl, isopropyl, n-butyl,    isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl, n-hexyl or    cyclohexyl radical. Alkyl radical having from 7 to 12 carbon atoms    preferably means the octyl, decyl, or dodecyl radical. Alkenyl    radical with 1 to 6 carbon atoms means hydrocarbon radicals having    at least one double bond between two carbon atoms, of the —CH═CH—    type, for example the ethenyl, propen-1-yl, propen-2-yl, buten-1-yl,    buten-2-yl, penten-1-yl, penten-2-yl, 3-methyl-buten-2-yl radical.    Alkynyl radical with 1 to 6 carbon atoms means hydrocarbon radicals    having at least one triple bond between two carbon atoms, of the    —C≡C— type, for example the ethynyl, propyn-1-yl, propyn-2-yl,    butyn-1-yl, butyn-2-yl, pentyn-1-yl or pentyn-2-yl radical.-   Halogen atom means an atom of fluorine, of chlorine, of bromine, or    of iodine.-   “Ring with n atoms” means, according to the invention, mono- or    poly-cyclic radicals whose cyclic moiety is formed by a total of n    atoms (in this case, n=3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14)    and preferably comprising 3 to 7 carbon atoms. This cyclic radical    can be saturated or unsaturated, optionally aromatic. It can be a    carbocycle, i.e. a ring whose cyclic part is formed exclusively of    carbon atoms. It can also be a heterocycle; in that case, at least    one of the atoms of the cyclic part is a heteroatom, such as    nitrogen, oxygen or sulfur. This definition of the rings according    to the invention, including phenyl, notably includes rings    substituted with one or more halogen atoms (and/or with one or more    hydroxyl, thiol, cyano, nitro functions, and/or with one or more    alkyl, alkenyl, alkyloxy, alkylthio radicals, having 1 to 6 carbon    atoms, and/or with one or more phenyl or phenylalkyl radicals with    the alkyl moiety having 1 to 3 carbon atoms, and said radicals    themselves can be halogenated (such as perfluoroalkyls, for example    —CF₃) and/or substituted with alkyl, alkenyl, alkyloxy, alkylthio    groups, and/or with hydroxyl, cyano, thiol, nitro functions. As    examples we may mention:    -   saturated carbocycles such as cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, norbornyl, adamantyl, or cycloheptyl;    -   unsaturated, aromatic or partially aromatic carbocycles, such as        cyclobutadiene, benzene (or phenyl group), pentalene, heptalene,        naphthalene, or anthracene; among the aromatic carbocyclic        groups, the phenyl or naphthyl group, substituted or        unsubstituted, is quite particularly preferred;    -   saturated heterocycles such as pyrrolidine, dioxane, morpholine,        piperidine, piperazine, 2-oxo-piperidine, or 2-oxo-pyrrolidine;    -   unsaturated, aromatic or nonaromatic heterocycles, such as        pyridine, furan, pyran, pyrrole, thiophene, isoxazole,        oxadiazole, oxazole, benzimidazole, indole, benzofuran,        hexamethylamine, tetrazole, indoline, isoindole, isoindoline,        benzothiophene, quinoline, or imidazole.-   The terms “alkyloxy” and “alkylthio” refer respectively to an alkyl    chain bound to the rest of the molecule via an oxygen atom (ether    bond) or to an alkyl chain bound to the rest of the molecule via a    sulfur atom (thioether bond). The term “alkyl” corresponds to the    definition given previously. As examples of alkoxy, we may mention    the methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy,    isobutyloxy, tert-butyloxy, sec-butyloxy or hexyloxy radicals. As    examples of alkylthio, we may mention the methylthio, ethylthio,    n-propylthio, isopropylthio, n-butylthio, isobutylthio,    tert-butylthio, sec-butylthio or hexylthio radicals.-   The term “phenylalkyl” denotes a radical of the alkyl type    substituted with a phenyl group, the alkyl radical being as defined    above. This definition notably includes phenylalkyl radicals whose    phenyl group is substituted with one or more halogen atoms and/or    with one or more alkyl radicals with 1 to 6 carbon atoms or alkenyl    radicals with 2 to 6 carbon atoms, optionally themselves    halogenated.-   The concept of “bioisosteres of the carboxyl radical” refers to    chemical groups functionally/biologically equivalent to a carboxyl    radical (—COOH), i.e. they can replace the carboxyl radical of a    compound without significantly changing the overall biological    activity of said compound. Bioisosteric groups are generally used    for improving the efficacy, selectivity, stability, or    pharmacokinetics of molecules. Numerous bioisosteric groups of the    carboxyl radical are known and are described extensively in the    literature (Burger A, 1991; Lima L M and Barreiro E J, 2005). This    applies notably to the following groups:

The alkyl radical R of the triazole can be an alkyl radical as definedpreviously.

-   The concept of “functions derived from the carboxylic acid function”    refers to functions susceptible to hydrolysis (notably to enzymatic    hydrolysis) known by a person skilled in the art as being precursors    of the carboxylic acid function. These functions are widely used for    modifying the pharmacokinetic properties of carboxylated active    molecules. They are notably esters, thioesters, amides and    thioamides.

In general, the invention relates to compounds corresponding to generalformula (I) as defined previously, in which, preferably:

-   G is selected from the methoxy, ethoxy, n-propyloxy, isopropyloxy,    n-butyloxy, tert-butyloxy, sec-butyloxy, n-pentyloxy,    cyclopentyloxy, n-hexyloxy, cyclohexyloxy, phenoxy, methylamine,    dimethylamine, ethylamine, diethylamine, n-propylamine,    dipropylamine, isopropylamine, diisopropylamine, n-butylamine,    dibutylamine, tert-butylamine, n-hexylamine, dihexylamine,    piperidine, pyrolidine, aniline, methylthio, ethylthio,    n-propylthio, isopropylthio, n-butylthio, tert-butylthio,    sec-butylthio, n-pentylthio, cyclopentylthio, n-hexylthio,    cyclohexylthio, thiophenol radicals; and/or-   X₁, X₂, X₃, X₄ and X₅ are selected independently from the hydrogen    atom, the methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy,    tert-butyloxy, sec-butyloxy, n-hexyloxy, cyclohexyloxy, phenoxy,    methylamine, dimethylamine, ethylamine, diethylamine, n-propylamine,    dipropylamine, isopropylamine, diisopropylamine, n-butylamine,    dibutylamine, tert-butylamine, n-hexylamine, dihexylamine,    piperidine, pyrolidine, aniline, methylthio, ethylthio,    n-propylthio, isopropylthio, n-butylthio, tert-butylthio,    sec-butylthio, n-pentylthio, cyclopentylthio, n-hexylthio,    cyclohexylthio, thiophenol, phenyl, benzyl, phenethyl,    2-methylphenyl, 3-m ethylphenyl, 4-methylphenyl, 2-methoxyphenyl,    3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl,    4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,    2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl,    3-iodophenyl, 4-iodophenyl, 2-(trifluoromethyl)phenyl,    3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl,    2-(trifluoromethoxy)phenyl, 3-(trifluoromethoxy)phenyl,    4-(trifluoromethoxy)phenyl, 2,6-dimethylphenyl, 3,6-dimethylphenyl,    4,6-dimethylphenyl, 5,6-dimethylphenyl, 2,6-fluorophenyl,    3,6-fluorophenyl, 4,6-fluorophenyl, 5,6-fluorophenyl,    2,6-dichlorophenyl, 3,6-dichlorophenyl, 4,6-dichlorophenyl,    5,6-dichlorophenyl, 2,6-bromophenyl, 3,6-bromophenyl,    4,6-bromophenyl, 5,6-bromophenyl, 2,6-iodophenyl, 3,6-iodophenyl,    4,6-iodophenyl, 5,6-iodophenyl, iodo, bromo, chloro, fluoro, nitro,    cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl,    isobutyl, tert-butyl, sec-butyl, cyclobutyl, pentyl, neopentyl,    cyclopentyl, n-hexyl, cyclohexyl, pyridyl, furyl, thienyl radicals;    and/or-   R₁ and R₂ can be selected independently from the hydrogen atom, the    methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl,    n-butyl, isobutyl, tert-butyl, sec-butyl, cyclobutyl, pentyl,    neopentyl, cyclopentyl, n-hexyl, cyclohexyl radicals; R₁ and R₂ can    also form, together and with the carbon atom to which they are    bound, a ring of the cyclopropyl, cyclobutyl, cyclopentyl or    cyclohexyl type; and/or-   R₃ and R₄ can be selected independently from the hydrogen atom, the    iodo, bromo, chloro, fluoro, methyl, trifluoromethyl, ethyl,    n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl,    sec-butyl, cyclobutyl, pentyl, neopentyl, cyclopentyl, n-hexyl,    cyclohexyl, phenyl, benzyl, phenethyl radicals; R₃ and R₄ can also    form, together and with the carbon atom to which they are bound, a    ring of the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl    type; and/or-   Y₁ can be selected from an oxygen, sulfur or selenium atom, or an    —NR, in which case R can be selected from the hydrogen atom, the    methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl,    n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl,    n-hexyl, phenyl, benzyl, phenethyl, 2-methylphenyl, 3-methylphenyl,    4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,    2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl,    3-chiorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl,    4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl,    2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)-phenyl,    4-(trifluoromethyl)phenyl, 2,6-dimethylphenyl, 3,6-dimethylphenyl,    4,6-dimethylphenyl, 5,6-dimethylphenyl, 2,6-fluorophenyl,    3,6-fluorophenyl, 4,6-fluorophenyl, 5,6-fluorophenyl,    2,6-dichlorophenyl, 3,6-dichlorophenyl, 4,6-dichlorophenyl,    5,6-dichlorophenyl, 2,6-bromophenyl, 3,6-bromophenyl,    4,6-bromophenyl, 5,6-bromophenyl, 2,6-iodophenyl, 3,6-iodophenyl,    4,6-iodophenyl, and 5,6-iodophenyl radicals, and/or-   Y₂ can be selected from an oxygen, sulfur or selenium atom, or a    —CR₅R₆, in which case R₅ and R₆ can be selected independently from    the hydrogen atom, the iodo, bromo, chloro, fluoro, methyl,    trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl,    isobutyl, tert-butyl, sec-butyl, cyclobutyl, pentyl, neopentyl,    cyclopentyl, n-hexyl, cyclohexyl, phenyl, benzyl, phenethyl,    2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl,    3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl,    4-fluorophenyl, 2-chiorophenyl, 3-chlorophenyl, 4-chlorophenyl,    2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl,    3-iodophenyl, 4-iodophenyl, 2-(trifluoromethyl)phenyl,    3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl,    2,6-dimethylphenyl, 3,6-dimethylphenyl, 4,6-dimethylphenyl,    5,6-dimethylphenyl, 2,6-fluorophenyl, 3,6-fluorophenyl,    4,6-fluorophenyl, 5,6-fluorophenyl, 2,6-dichlorophenyl,    3,6-dichlorophenyl, 4,6-dichlorophenyl, 5,6-dichlorophenyl,    2,6-bromophenyl, 3,6-bromophenyl, 4,6-bromophenyl, 5,6-bromophenyl,    2,6-iodophenyl, 3,6-iodophenyl, 4,6-iodophenyl, 5,6-iodophenyl,    pyridyl, furyl, thienyl, methoxy, ethoxy, n-propyloxy, isopropyloxy,    n-butyloxy, tert-butyloxy, sec-butyloxy, n-hexyloxy, cyclohexyloxy,    phenoxy, methylamine, dimethylamine, ethylamine, diethylamine,    n-propylamine, dipropylamine, isopropylamine, diisopropylamine,    n-butylamine, dibutylamine, tert-butylamine, n-hexylamine,    dihexylamine, piperidine, pyrolidine, aniline, methylthio,    ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio,    sec-butylthio, n-pentylthio, cyclopentylthio, n-hexylthio,    cyclohexylthio, and thiophenol radicals; R₅ and R₆ can also form,    together and with the carbon atom to which they are bound, a ring of    the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl type; and/or-   W is a carboxyl radical, a derivative function (notably the methyl    ester, ethyl ester, propyl ester, isobutyl ester, tert-butyl ester)    or a bioisosteric group of the carboxylic acid function.

The invention relates more preferably to compounds of general formula(I) as previously defined and in which at least one of the followingconditions is satisfied:

-   Y₂ is located meta or para of Y₁ and even more preferably Y₂ is    located para of Y₁; and/or-   X₃ denotes a hydrogen atom and even more preferably X₃ and X₂ denote    simultaneously a hydrogen atom or X₃ and X₁ denote simultaneously a    hydrogen atom; and/or-   X₄ and X₅ denote independently a hydrogen atom, an alkyl radical    having 1 to 6 carbon atoms, or a group —OR″_(a) or —SR″_(a) (R″_(a)    being an alkyl radical having 1 to 6 carbon atoms); and/or-   R₁, R₂, R₃, R₄ denote independently a hydrogen atom or a methyl,    ethyl, propyl, butyl, isopropyl or tert-butyl radical; and/or-   X₃, R₁ and R₂ denote simultaneously hydrogen atoms; and/or-   X₁ and/or X₂ denote a ring with 5 to 14, preferably 5 to 10, atoms,    unsubstituted or substituted with a —CF₃ group, and even more    preferably a phenyl, furanyl or naphthalenyl radical, unsubstituted    or substituted with a —CF₃ group; and/or-   G denotes a radical —OR_(a) or —SR_(a), with R_(a) selected from an    alkyl radical having 1 to 6 carbon atoms, a cyclohexyl or a phenyl    radical; or alternatively G denotes a radical —NR_(a)R_(b), R_(a)    and R_(b) forming together, and with the nitrogen atom to which they    are bound, a heterocycle with 3 to 8 atoms (notably, a piperidinyl    radical); and/or-   G denotes a radical —OR_(a) with R_(a) selected from a methyl,    ethyl, propyl, butyl, isopropyl or tert-butyl radical.

A first particular aspect of the invention relates to compounds ofgeneral formula (I) in which Y₁ denotes an oxygen or sulfur atom andsimultaneously Y₂ denotes an oxygen atom, a sulfur atom or a group—CR₅R₆ in which R₅ and R₆, which may be identical or different, areselected from a hydrogen atom, an alkyl radical with 1 to 6 carbonatoms, an alkenyl or alkynyl radical with 2 to 6 carbon atoms, and aring with 3 to 6 atoms, the ring preferably being phenyl.

A second particular aspect of the invention relates to compounds ofgeneral formula (I) in which Y₁ denotes an amino group —NH. According tothis second particular aspect of the invention, Y₂ preferably representsan oxygen atom, a sulfur atom or a radical —CR₅R₆—, in which R₅ and R₆,which may be identical or different, are selected from a hydrogen atom,an alkyl radical with 1 to 6 carbon atoms, an alkenyl or alkynyl radicalwith 2 to 6 carbon atoms, and a ring with 3 to 6 atoms, the ringpreferably being phenyl.

According to this first or second particular aspect of the invention, X₁preferably denotes an unsubstituted phenyl radical or a phenyl radicalsubstituted with a —CF₃ group, said group —CF₃ being preferably in paraof the pyridinyl radical, and/or G denotes a group —OCH₃ or —OC(CH₃)₃.More specifically, X₁ advantageously denotes a phenyl radicalsubstituted with a —CF₃ group in para of the pyridinyl radical, Gdenotes a group —OCH₃, and X₂ denotes a hydrogen atom. According to oneembodiment of this first particular aspect of the invention, X₁advantageously denotes an unsubstituted phenyl radical, G denotes agroup —OC(CH₃)₃, and X₂ denotes a hydrogen atom. Whether they arecompounds belonging to said first particular aspect of the invention orto said second particular aspect of the invention, advantageously R₁,R₂, R₃ and R₄ denote simultaneously hydrogen atoms.

A third particular aspect of the invention relates to compounds ofgeneral formula (I) which

-   are identified and classified based on the structural    characteristics as defined in FIGS. 7 g, 7 h and 7 i; and/or-   display the activities as established in Examples 8 to 12, and more    specifically in Table 8-1 and FIGS. 8 to 12.

The present invention relates to compounds that are activators of PPARs.These compounds meet the pharmacological criteria stated in theliterature for compounds of this kind, by measuring various parameterssuch as the properties of activating human PPARs in vitro and incellular models, and antidiabetic or hypolipemic character in vivo inmurine models. These results show that the compounds of general formula(I) having specific groups have properties that are superior andunexpected relative to documents of the prior art mentioning similarcompounds, such as WO 03/084916, WO 08/152333, WO 05/041959, WO08/066356, EP 1266888, and US 2005096336. For example, properties ofactivating PPARδ were confirmed in vivo and in vitro for Cpd 24 and Cpd7 (see Table 8-1, Example 11, and FIG. 11), which form part of the samegroup of compounds according to the invention (see Cpd 2 in FIG. 7 g,which was evaluated in Example 9). Moreover, properties of activatingPPARγ were confirmed in vivo and in vitro for Cpd 19 and Cpd 36 (seeTable 8-1, Example 12, and FIG. 12), which form part of the same groupof compounds according to the invention (see FIG. 7 i).

Preferably, the compounds according to the invention are selected from:

-   Cpd 1:    2-(4-((2-methoxy-6-phenylpyridin-3-yl)methoxy)phenoxy)-2-methyl-propanoic    acid-   Cpd 2:    2-(4-((2-methoxy-6-phenylpyridin-3-yl)methoxy)phenoxy)ethanoic acid-   Cpd 3:    2-(4-((2-methoxy-6-phenylpyridin-3-yl)methoxy)phenoxy)propanoic acid-   Cpd 4:    2-(4-(((2-methoxy-6-phenylpyridin-3yl)methyl)amino)phenoxy)ethanoic    acid-   Cpd 5:    2-(4-(((2-methoxy-6-phenylpyridin-3yl)methyl)amino)phenoxy)propanoic    acid-   Cpd 6:    2-(4-((2-tert-butyloxy-6-phenylpyridin-3-yl)methoxy)phenoxy)-2-methyl-propanoic    acid-   Cpd 7:    2-(4-(((2-tert-butyloxy-6-phenylpyridin-3-yl)methoxy)phenoxy)ethanoic    acid-   Cpd 8:    2-(4-((2-tert-butyloxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)ethanoic    acid-   Cpd 9:    2-(4-(((2-tert-butyloxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)-2-methyl-propanoic    acid-   Cpd 10:    2-(4-(((2-tert-butyloxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)propanoic    acid-   Cpd 11:    2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenylthio)-2-methyl-propanoic    acid-   Cpd 12:    2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)-2-methyl-propanoic    acid-   Cpd 13:    2-(3-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)-2-methyl-propanoic    acid-   Cpd 14:    2-(3-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)ethanoic    acid-   Cpd 15:    2-(4-((2-hexyloxy-6-phenylpyridin-3-yl)methoxy)phenoxy)ethanoic acid-   Cpd 16:    2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenylthio)ethanoic    acid-   Cpd 17:    2-(4-((2-hexyloxy-6-phenylpyridin-3-yl)methoxy)phenoxy)-2-methyl-propanoic    acid-   Cpd 18:    2-(4-((2-cyclohexyloxy-6-phenylpyridin-3-yl)methoxy)phenoxy)ethanoic    acid-   Cpd 19:    3-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenyl)propanoic    acid-   Cpd 20:    2-(4-((6-phenyl-2-(piperidin-1-yl)pyridin-3-yl)methoxy)phenoxy)ethanoic    acid-   Cpd 21:    2-(4-((2-methoxy-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methoxy)-phenoxy)-2-methylpropanoic    acid-   Cpd 22:    2-(4-(((2-methoxy-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)-phenylthio)-2-methylpropanoic    acid-   Cpd 23:    2-(4-(((2-methoxy-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)-phenylthio)ethanoic    acid-   Cpd 24:    2-(4-((2-methoxy-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methoxy)-phenoxy)ethanoic    acid-   Cpd 25:    2-(4-((2-phenylthio-6-(phenyl)pyridin-3-yl)methoxy)phenoxy)ethanoic    acid-   Cpd 26:    2-(4-(((2-methoxy-5-phenylpyridin-3-yl)methyl)amino)phenylthio)ethanoic    acid-   Cpd 27:    2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenylthio)-2,2-difluoroethanoic    acid-   Cpd 28:    2-(4-(((2-methoxy-5,6-diphenylpyridin-3-yl)methyl)amino)phenylthio)ethanoic    acid-   Cpd 29: 2-(4-(((2-methoxy-5-bromo-6-phenylpyridin-3-yl)methyl)amino)    phenylthio)-ethanoic acid-   Cpd 30:    2-(4-(((2-methoxy-6-furylpyridin-3-yl)methyl)amino)phenylthio)ethanoic    acid-   Cpd 31:    3-(4-(((2-methoxy-6-furylpyridin-3-yl)methyl)amino)phenyl)propanoic    acid-   Cpd 32:    2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenylthio)-2-phenyl-acid-   Cpd 33:    3-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)(methyl)amino)phenyl)-propanoic    acid-   Cpd 34:    3-(4-(1-((2-methoxy-6-phenylpyridin-3-yl)propyl)amino)phenyl)propanoic    acid-   Cpd 35:    2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)-2,6-dimethyl-phenoxy)ethanoic    acid-   Cpd 36:    3-(4-(((2-methoxy-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)-phenyl)propanoic    acid-   Cpd 37:    3-(4-((2-methoxy-6-phenylpyridin-3-yl)methylthio)phenyl)propanoic    acid-   Cpd 38:    3-(4-(((2-(ethylthio)-6-phenylpyridin-3-yl)methyl)amino)phenyl)propanoic    acid-   Cpd 39:    3-(4-(((2-methoxy-6-(parabiphenyl)pyridin-3-yl)methyl)amino)phenyl)-propanoic    acid-   Cpd 40:    3-(4-(((2-methoxy-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)-phenyl)propanoic    acid-   Cpd 41:    3-(4-(((2-methoxy-5-phenylpyridin-3-yl)methyl)amino)phenyl)propanoic    acid-   Cpd 42:    3-(4-((2(-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenyl)-3-phenyl-propanoic    acid-   Cpd 43:    3-(2-methoxy-4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)-phenyl)-propanoic    acid-   Cpd 44:    3-(3-methoxy-4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)-phenyl)-propanoic    acid-   Cpd 45:    3-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenyl)butanoic    acid-   Cpd 46:    3-(4-(((2-methoxy-5-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)phenyl)propanoic    acid-   Cpd 47:    3-(4-(((2-methoxy-5-(3-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)-phenyl)propanoic    acid-   Cpd 48:    3-(4-(((2,6-dimethoxy-5-phenylpyridin-3-yl)methyl)amino)phenyl)propanoic    acid-   Cpd 49:    3-(4-(((5-(4-chlorophenyl)-2-methoxypyridin-3-yl)methyl)amino)phenyl)-propanoic    acid-   Cpd 50:    3-(4-(((2-methoxy-5-(naphthalen-2-yl)pyridin-3-yl)methyl)amino)phenyl)-propanoic    acid-   Cpd 51:    3-(4-(((2-ethoxy-6-phenylpyridin-3-yl)methyl)amino)phenyl)propanoic    acid-   Cpd 52:    3-(4-((2-methoxy-5-phenylpyridin-3-yl)methoxy)phenyl)hex-4-ynoic    acid-   Cpd 53:    3-(4-((2-methoxy-6-phenylpyridin-3-yl)methoxy)phenyl)hex-4-ynoic    acid-   Cpd 54:    3-(4-(((2-isopropyloxy-6-phenylpyridin-3-yl)methyl)amino)phenyl)propanoic    acid.

Even if the compounds according to the invention can be generated andpurified according to methods and with compounds already known by aperson skilled in the art and such as those described in the literature,the invention relates to methods of preparation of the compounds ofgeneral formula (I).

According to a first variant of the method of preparation (FIGS. 7 a, 7b and 7 c), the compounds of general formula (I) can be obtained by aseries of reactions consisting of reacting intermediates of the phenol,thiophenol, or aniline type according to the invention with one of theintermediates of the pyridine 3-carboxaldehyde or ketone type accordingto the invention.

According to a second variant of the method of preparation (FIGS. 7 d, 7e and 7 f), the compounds of general formula (I) can be obtained by aseries of reactions consisting of reacting intermediates of the phenol,thiophenol, or aniline type according to the invention with one of theintermediates of the 3-hydroxymethyl-, 3-halomethyl- or3-arylsulfonylmethyl-pyridine type according to the invention.

The details of the general methods of synthesis and purification of theraw reaction products obtained are defined in Example 1. Moreparticularly, Examples 1 to 7 show how different series of compoundsaccording to the invention, and the corresponding reactionintermediates, can be synthesized and purified from compounds that arealready known. A general scheme of synthesis of the compounds of generalformula (I) is presented in FIG. 1 but a person skilled in the art willbe able to synthesize said compounds with other methods and compoundsalready known, notably to obtain reaction intermediates and/or compoundswith specific groups G, R, R₁-R₆, R/′/″/′″_(a), R/′/″/′″_(b), X₁-X₆and/or Y₁, Y₂.

The functional groups optionally present in the reaction intermediatesused in the methods can be protected, either permanently, ortemporarily, by protective groups, which ensure unequivocal synthesis ofthe desired compounds. The reactions of protection and deprotection arecarried out according to techniques well known by a person skilled inthe art or such as those described in the literature, as in the book“Greene's Protective Groups in Organic Synthesis” (4th edition, 2007;edited by Wuts P G and Greene T W; published by John Wiley and Sons).

The compounds according to the invention can contain one or moreasymmetric centers. The present invention includes stereoisomers(diastereoisomers, enantiomers), pure or mixed, as well as racemicmixtures and geometric isomers, or tautomers. When an enantiomericallypure (or enriched) mixture is desired, it can be obtained either bypurification of the final product or of chiral intermediates, or byasymmetric synthesis according to methods known by a person skilled inthe art (using for example chiral reactants and catalysts). Certaincompounds according to the invention can have various stable tautomericforms and all these forms and mixtures thereof are included in theinvention. The techniques for obtaining and characterizing thestereoisomers, pure or mixed, as well as racemic mixtures and geometricisomers, or tautomers are described in the literature, such as in thebook “Chirality in Drug Design and Development” (2004; edited by Reddy IK and Mihvar R; Published by CRC Press).

The compounds of general formula (I) can exist in the form of bases orof salts of addition to acids. These salts can be prepared, selected andused according to techniques well known by a person skilled in the artor as described in the literature such as in the book “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” (2002; edited byStahl P H and Wermuth G H; published by VHCA Switzerland and Wiley-VCHGermany). Notably, the present invention relates to the“pharmaceutically acceptable” salts of the compounds according to theinvention. Generally, this term denotes salts of low toxicity ornontoxic obtained from bases or from acids, organic or inorganic.

These salts can be obtained during the stage of final purification ofthe compound according to the invention or by incorporation of the salton the compound already purified. These salts can be prepared withpharmaceutically acceptable acids but the salts of other acids usefulfor purifying or isolating the compounds of general formula (I) alsoform part of the invention. In particular, when the compounds accordingto the invention are in the form of a salt, it is a salt of an alkalimetal, in particular a salt of sodium or of potassium, or a salt of analkaline-earth metal, in particular magnesium or calcium, or a salt withan organic amine, more particularly with an amino acid such as arginineor lysine.

More particularly, group W as described previously can have an acidcharacter. The corresponding salts are selected from metal salts (forexample, aluminum, zinc, chromium), alkaline salts (for example,lithium, sodium, potassium) or alkaline-earth (for example, calcium,magnesium). They can for example be organic salts such as nontoxicammonium derivatives and amines: ammonium, quaternary ammonium (forexample, tetramethylammonium, tetraethylammonium), alkylamines (forexample, methylamine, dimethylamine, trimethylamine, triethylamine,ethylamine, etc.), hydroxyalkylamines (for example, 2-hydroxyethylamine,bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, etc.),cycloalkylamines (for example, bicyclohexylamine, glucamine, etc.),pyridines and analogs (such as collidine, quinine, quinoline, etc.) ofsalts of amino acids with basic character (for example, lysine,arginine, etc.).

The pyridine nucleus, the groups G and/or Y₁ as described previously canhave a basic character. The corresponding salts are selectedadvantageously from mineral acids (hydrochloric, hydrobromic, sulfuric,boric, nitric, phosphoric, etc.) or organic acids (for example,carboxylic or sulfonic acids such as formic, acetic, methylsulfonic,propionic, toluenesulfonic, valeric, oleic, palmitic, stearic, lactic,lauric, oxalic, citric, maleic, succinic, glycolic, tartaric acid, etc.)or salts obtained from amino acids with acid character such as glutamicacid.

Certain compounds according to the invention can be isolated in the formof zwitterions and each of these forms is included in the invention, aswell as mixtures thereof. Certain compounds according to the inventionand their salts can be stable in several solid forms. The presentinvention includes all solid forms of the compounds according to theinvention, which includes the amorphous, polymorphic, mono- andpoly-crystalline forms.

The compounds of general formula (I) can exist in the free form or inthe solvated form, i.e. in the form of associations or combinations withone or more molecules of a solvent, for example with pharmaceuticallyacceptable solvents such as water (hydrates) or ethanol. The presentinvention also includes the prodrugs of the compounds according to theinvention which, after administration to a subject, are converted to thecompounds as described in the invention or to their metabolites havingtherapeutic activities comparable to the compounds according to theinvention.

The compounds according to the invention labeled with one or moreisotopes are also included in the invention: these compounds arestructurally identical but differ in that at least one atom of thestructure is replaced by an isotope (radioactive or not). Examples ofisotopes that can be included in the structure of the compoundsaccording to the invention can be selected from hydrogen, carbon,nitrogen, oxygen, sulfur such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵Srespectively. The radioactive isotopes ³H and ¹⁴C are particularlypreferred as they are easy to prepare and detect in studies of thebioavailability in vivo of the substances. The heavy isotopes (such as²H) are particularly preferred as they are used as internal standards inanalytical studies.

The present invention also relates to the compounds as describedpreviously, as medicinal products. Notably the present invention relatesto the use of a compound according to the invention in the manufactureof a medicinal product intended for the therapeutic and/or prophylactictreatment of diabetes, dyslipidemias, insulin resistance, pathologiesassociated with metabolic syndrome, atherosclerosis, and cardiovasculardiseases (notably those associated with disorders of lipid and/orcarbohydrate metabolism), obesity, hypertension and/or inflammatorydiseases.

The present invention also relates to a pharmaceutical compositioncomprising, in a pharmaceutically acceptable carrier, at least onecompound as described above, optionally in combination with one or moreother therapeutic and/or cosmetic active principles. Advantageously itis a pharmaceutical composition for the therapeutic and/or prophylactictreatment of diabetes, dyslipidemias, insulin resistance, pathologiesassociated with metabolic syndrome, atherosclerosis, cardiovasculardiseases, obesity, hypertension, inflammatory diseases, etc. Theinflammatory pathologies denote asthma in particular. Preferably it is apharmaceutical composition for preventing and/or treating cardiovascularrisk factors associated with disorders of lipid and/or carbohydratemetabolism (hyperlipidemia, type 2 diabetes, obesity etc.) reducing theglobal risk, with PPAR activating compounds as described in theliterature (Glide A J et al., 2006; Blaschke F et al., 2006).

Another object of the invention relates to a nutritional compositioncomprising at least one compound as described above.

Within the scope of the present invention and generally,“pharmaceutically acceptable carrier” means substances such asexcipients, vehicles, adjuvants, buffers that are used conventionally,in combination with the active principle(s), for preparing a medicinalproduct. The choice of said carriers depends essentially on the route ofadministration envisaged.

Another object of the invention is the use of at least one compound asdescribed previously for preparing pharmaceutical compositions intendedfor the therapeutic and/or prophylactic treatment of variouspathologies, notably associated with disorders of metabolism, amongwhich we may mention diabetes (in particular, type 2 diabetes),dyslipidemias, insulin resistance, pathologies associated with metabolicsyndrome X, atherosclerosis, cardiovascular diseases, obesity,hypertension, inflammatory diseases.

As an example, the compounds according to the invention, like theinsulin-secreting compounds and PPAR activating compounds currentlymarketed for the treatment of metabolic diseases, can advantageously beadministered in combination with one or more other therapeutic and/orcosmetic agents, marketed or under development, such as:

-   antidiabetic drugs: insulin secretors (such as sulfonylureas and    glinides etc.), inhibitors of alpha-glucosidase, PPARγ agonists    (such as thiazolidinediones etc.), dual PPARα/PPARγ agonists,    pan-PPAR agonists (compounds simultaneously activating the 3 PPAR    isoforms), biguanides, inhibitors of Dipeptidyl Peptidase IV,    agonists of Glucagon-Like Peptide-1 (such as exenatide), inhibitors    of alpha-glucosidase, as well as insulin and insulin analogs;-   hypolipemic and/or hypocholesterolemic molecules: fibrates (such as    fenofibrate and gemfibrozil), inhibitors of hydroxylmethylglutaryl    Coenzyme A reductase (such as statins), inhibitors of cholesterol    absorption (such as ezetimibe and phytosterols), inhibitors of    Cholesteryl Ester Transfer Protein, inhibitors of    Acyl-CoA:Cholesterol O-Acyl Transferase (ACAT), inhibitors of    Microsomal Triglyceride Transfer Protein, sequestering agents of    biliary acids, vitamin E, polyunsaturated fatty acids, omega 3 fatty    acids, derivatives of the nicotinic acid type (niacin);-   antihypertensive agents and hypotensive agents:    angiotensin-converting enzyme inhibitors (such as captopril and    enalapril), antagonists of the angiotensin II receptor (such as    losartan and irbesartan), beta-blockers (such as atenolol and    propranolol), thiazide and nonthiazide diuretics, vasodilators,    calcium channel blockers (such as nifedipine and verapamil);-   antiplatelet agents (such as aspirin and clopidogrel);-   anti-obesity agents: sibutramine, lipase inhibitors (orlistat),    PPARδ agonists and antagonists, antagonists of the CB1 cannabinoid    receptor, dopamine agonists, agonists of leptin receptors, serotonin    reuptake inhibitors, beta-3 agonists, CCK-A agonists, NPY    inhibitors, agonists of MC4 receptors, antagonists of melanin    concentrating hormone receptors, antagonists of orexine, inhibitors    of phosphodiesterases, inhibitors of 11-β-hydroxy steroid    dehydrogenase, inhibitors of dipeptidyl peptidase IV, antagonists    (or inverse agonists) of histamine H3, derivatives of ciliary    neurotrophic factor, agonists of growth hormone secretagogue    receptors, modulators of ghreline, inhibitors of diacyglycerol    acyltransferase;-   anti-inflammatory agents: corticoids (such as prednisone and    hydrocortisone), nonsteroidal anti-inflammatories (derivatives of    indole, of the arylcarboxylic group, derivatives of oxicam, or of    the fenamate group), selective inhibitors of COX2 (such as celecoxib    or rofecoxib);-   antioxidants: for example probucol;-   agents used in the treatment of heart failure: thiazide or    nonthiazide diuretics, angiotensin converting enzyme inhibitors,    digitalis glucosides, beta-blockers, phosphodiesterase inhibitors;-   agents used for treating coronary insufficiency: beta-blockers,    calcium channel blockers, NO donors, amiodarone,-   anti-asthmatic drugs: bronchodilators (beta 2 receptor agonists),    corticoids, cromoglycate, leukotriene receptor antagonists;-   corticoids used in the treatment of skin pathologies such as    psoriasis and dermatitis;-   vasodilators and/or anti-ischemic agents.

The invention also relates to a method of therapeutic and/orprophylactic treatment of diabetes, dyslipidemias, insulin resistance,pathologies associated with metabolic syndrome, atherosclerosis,cardiovascular diseases (notably those associated with disorders oflipid and/or carbohydrate metabolism), obesity, hypertension and/orinflammatory diseases, comprising the administration to a subject,notably human, of an effective amount of a compound or of apharmaceutical composition as defined previously. In the sense of theinvention the term “an effective amount” refers to an amount of thecompound sufficient to produce the desired biological result, preferablynontoxic. In the sense of the invention the term “subject” means amammal and more particularly a human.

The term “treatment” denotes therapeutic, symptomatic, and/orprophylactic treatment. The compounds of the invention can thus be usedin subjects (in particular human) affected by a declared disease. Thecompounds of the invention can also be used for delaying or slowing theprogression or preventing further progression of the disease, thusimproving the condition of the subjects. The compounds of the inventioncan finally be administered to persons who are not ill, but who mightnormally develop the disease or who have a high risk of developing thedisease.

According to another aspect of the invention, the compound of generalformula (I), or one of its salts of addition to a pharmaceuticallyacceptable acid or one of its solvates or hydrates and anothertherapeutic agent can be administered simultaneously (in one and thesame pharmaceutical form), separately (with administration, at the sametime, of both compounds but each comprised in a separate pharmaceuticalform) or spread over time (with the administration, at different times,of the two compounds, generally during a time interval not exceeding 24hours).

The pharmaceutical compositions according to the inventionadvantageously comprise one or more pharmaceutically acceptableexcipients or vehicles. We may mention for example saline,physiological, isotonic, buffered, etc. solutions, compatible withpharmaceutical use and known by a person skilled in the art. Thecompositions can contain one or more agents or vehicles selected fromdispersants, solubilizers, stabilizers, preservatives, emulsifiers,antioxidants, emollients, hydrating agents, wetting agents, forimproving the flavor, for regulating the hydration or pH, etc. Agents orvehicles usable in formulations (liquid and/or injectable and/or solid)are notably methylcellulose, hydroxymethylcellulose,carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose,certain vegetable or animal oils, acacia, dextrose, sucrose, gelatin,agar, stearic acid, liposomes, etc. The compositions can be formulatedin the form of injectable suspensions, gels, oils, tablets,suppositories, powders, hard capsules, soft capsules, aerosols, etc.,optionally by means of galenic forms or devices providing prolongedand/or delayed release. For this type of formulation, an agent, such ascellulose, carbonates or starches, is advantageously used. As anexample, a unit dosage form of a compound according to the invention inthe form of a tablet can comprise the following components: mannitol,croscarmellose sodium, maize starch, hydroxypropyl-methylcellulose,magnesium stearate.

The compounds or compositions according to the invention can beadministered in various ways and in various forms. Thus, they can forexample be administered systemically, by the oral, parenteral, topical,ocular, rectal, perlingual route, by inhalation or by injection, forexample by the intravenous, intramuscular, subcutaneous, transdermal,intraarterial route, etc. For injections, the compounds are generallypackaged in the form of liquid suspensions, which can be injected bymeans of syringes or by perfusion. For the oral route, the compositioncan be in the form of tablets, capsules, coated tablets, syrups,suspensions, solutions, powders, granules, emulsions, suspensions ofmicrospheres or nanospheres or of lipid or polymer vesicles forcontrolled release. For the parenteral route, the composition can be inthe form of solutions or suspensions for perfusion or for injection.

Of course, a person skilled in the art will take care to select thepossible compound or compounds to be added to these compositions in sucha way that the advantageous properties intrinsically attaching to thepresent invention are not or substantially not altered by the additionenvisaged, as is also explained in the literature, for example in thebook “Pharmaceutical Dosage Forms and Drug Delivery” (2007; edited byMahato R; published by CRC Press).

It is understood that the flow rate and/or the dose injected can beadapted by a person skilled in the art in relation to the patient's sex,age and weight, the pathology, the method of administration, or anyconcomitant treatments. Typically, the compounds are administered atdoses that can vary between 1 μg and 2 g per administration, preferablyfrom 0.1 mg to 1 g per administration. The administrations can be dailyor even repeated several times per day, if necessary. Furthermore, thecompositions according to the invention can additionally comprise otheragents or active principles. The compounds are used at a concentrationgenerally between 0.001% and 10 wt. %, preferably between 0.01% and 1wt. %, relative to the weight of the composition.

ABBREVIATIONS

-   ACO: Acyl-CoenzymeA oxidase-   ApoCIII: Apolipoprotein CIII-   Cpd: Compound-   CPT1b: Carnitine Palmitoyl Transferase 1b-   Ctrl: Control-   Et: Ethyl-   Stg.: Stage-   Ex. Example-   G: Group in general formula (I)-   HDL-cholesterol: High Density Lipoprotein cholesterol-   HOMA: Homeostatic Model Assessment-   Int.: Intermediate-   mpk: mg/kg/day-   OMe: O-Methyl-   OtBu: O-Tert-butyl-   PDK4: Pyruvate Dehydrogenase Kinase, isoform 4-   Ph: Phenyl-   Prot. Protocol-   PPAR: Peroxisome proliferator-activated receptor-   R, R₁-R₆, R/′/″/′″_(a), R/′/″/′″_(b) Groups in general formula (I)-   SEt: S-Ethyl-   tBu: Tert-butyl-   TG: Triglycerides-   UCP2: Uncoupling Protein 2-   X₁-X₆: Groups in general formula (I)-   Y₁, Y₂: Groups in general formula (I)

Statistical Analyses

The statistical analyses of the various pharmacological experimentsconsist of a Student t-test. The results are expressed relative to thecontrol group according to the p-value: p<0.05 (marked *); p<0.01(marked **); p<0.001 (marked ***).

LEGENDS OF THE FIGURES

FIG. 1—General Scheme for Synthesis of the Compounds According to theInvention

Except for specific compounds as stated in Examples 1 to 7, theintermediates generated in Example 2 (FIG. 2) were used for synthesizingthe intermediates in Example 3 (FIG. 3). The latter were used forsynthesizing the intermediates in Example 4 (FIG. 4), which were thenused for synthesizing the intermediates in Example 5 (FIG. 5). Theintermediates in Example 6 (FIG. 6) were generated separately. Asdescribed in Example 7 (FIG. 7), the compounds according to theinvention were synthesized using either the intermediates from Example 4and Example 6 or the intermediates from Example 5 and Example 6.

FIG. 2—Intermediates of the 2-oxo-1.2-dihydropyridine Type

Reaction scheme for synthesis of the intermediates in Example 2: Ex.2-1, 2-2 and 2-5 to 2-7 (FIG. 2 a); 2-3 (FIG. 2 b); 2-4 (FIG. 2 c).These intermediates can be classified according to their groups X₁, X₂and X₃ (FIG. 2 d).

FIG. 3—Intermediates of the alkoxy, alkylthio-, alkylamino-,halo-pyridine Type

Reaction scheme for synthesis of the intermediates in Example 3: Ex. 3-1to 3-4, 3-7, 3-9, 3-12, 3-13, 3-15, 3-16, 3-24 and 3-25 (FIG. 3 a);3-10, 3-11, 3-3-23 (FIG. 3 b); 3-5, 3-6, 3-8 and 3-14 (FIG. 3 c). Theseintermediates can be classified according to their groups X₁, X₂ and X₃(FIGS. 3 d and 3 e).

FIG. 4—Intermediates of the 3-hydroxymethyl-, 3-halomethyl- and3-arylsulfonylmethyl-pyridine type

Reaction scheme for synthesis of the intermediates in Example 4: Ex. 4-1to 4-10, 4-12, 4-13, 4.14, 4-17 to 4-23 (FIG. 4 a); 4-15 (FIG. 4 b);4-11 (FIG. 4 c); 4-16 (FIG. 4 d). These intermediates can be classifiedaccording to their groups X₁, X₂ and X₃ (FIGS. 4 e and 4 f).

FIG. 5—Intermediates of the Pyridine 3-carboxaldehyde and Ketone Type

Reaction scheme for synthesis of the intermediates in Example 5: Ex.5-1, 5-3, 5-4, 5-6 to 5-18 (FIG. 5 a); 5-2 (FIG. 5 b); 5-5 (FIG. 5 c).These intermediates can be classified according to their groups X₁, X₂and X₃ (FIGS. 5 d and 5 e).

FIG. 6—Intermediates of the Phenol, Thiophenol and Aniline Type

Reaction scheme for synthesis of the intermediates in Example 6: Ex. 6-1to 6-6, 6-11 to 6-13, and 6-20 (FIG. 6 a); 6-10, 6-14, 6-16 to 6-19(FIG. 6 b); 6-7 to 6-9 (FIG. 6 c); 6-15 (FIG. 6 d); 6-21 to 6-24 (FIG. 6e). These intermediates can be classified according to their groups Y₁and Y₂ (FIGS. 6 f and 6 g).

FIG. 7—Compounds According to the Invention

Reaction scheme for synthesis of the compounds according to theinvention: Cpd 4, Cpd 8-12, Cpd 16, Cpd 19, Cpd 22, Cpd 23, Cpd 26-32,Cpd 35, Cpd 36, Cpd 38-51, and Cpd 54 (FIG. 7 a); Cpd 13 and Cpd 14(FIG. 7 b); Cpd 34 (FIG. 7 c); Cpd 2, Cpd 6, Cpd 7, Cpd 15, Cpd 17, Cpd18, Cpd 20, Cpd 21, Cpd 24, Cpd 25, Cpd 52, Cpd 53 (FIG. 7 d); Cpd 1,Cpd 3, Cpd 5, Cpd 33 (FIG. 7 e); Cpd 37 (FIG. 7 f). The compoundsaccording to the invention can be classified according to their groupsX₁, X₂, X₃, Y₁ and Y₂ (FIGS. 7 g, 7 h, and 7 i).

FIG. 8—Antidiabetic Character of the Compounds According to theInvention

The effect of Cpd 24 was evaluated in vivo in the db/db mouse. Theplasma levels of glucose (FIG. 8 a), of insulin (FIG. 8 b), and the HOMAindex (FIG. 8 c) were measured after 8 days of treatment with Cpd 24administered at 30 mpk in the db/db mouse. The difference measuredprovides evidence of the effect of Cpd 24 on the parameters of insulinresistance. A decrease in the HOMA index, calculated on the basis ofthese plasma parameters, also reflects an improvement in sensitivity toinsulin.

The effect of Cpd 24 was also evaluated by measuring glucose tolerance.Glycemia was measured in the db/db mouse treated with Cpd 24,administered at 30 mpk for 9 days, after oral administration of a singledose of glucose (day 0), to obtain the kinetic curves of glycemia (FIG.8 d; the areas under the curves of the glucose tolerance test are shownin FIG. 8 e). The corrective action of Cpd 24 on insulin resistance isreflected in an improvement in glucose tolerance. The levels arecompared with those obtained in control animals (untreated).

FIG. 9—Hypolipemic Properties and Stimulating Effect on the Synthesis ofHDL-Cholesterol of the Compounds According to the Invention

The plasma levels of total cholesterol (FIG. 9 a) and of HDL-cholesterol(FIG. 9 b) were measured in the ApoE2/E2 dyslipidemic mouse after 7 daysof treatment with Cpd 2 or Cpd 4 by the oral route, administered at 10and 100 mpk. These parameters are compared with those obtained incontrol animals (untreated): the difference measured provides evidenceof the hypolipemic effect of the compounds according to the invention.

The effect of Cpd 2 and Cpd 4 was also evaluated in hepatic tissue ofthe ApoE2/E2 mouse by measuring the expression of genes involved inlipid and/or carbohydrate metabolism such as ACO (FIG. 9 c), PDK4 (FIG.9 d) and Apo CIII (FIG. 9 e). The levels of expression of each gene arenormal relative to the level of expression of the 36B4 reference gene.These parameters are compared with those obtained in control animals(untreated): the induction factor, i.e. ratio of the relative signal(induced by the compound according to the invention) to the mean of therelative values of the control group, is then calculated. The higherthis factor, the greater the gene expression activating character of thecompound. The final result is given as the mean of the induction valuesin each experimental group.

FIG. 10—Hypolipemic Properties of the Compounds According to theInvention

The plasma levels of total cholesterol (FIG. 10 a) and of free fattyacids (FIG. 10 b) were measured in the E2/E2 dyslipidemic mouse after 7days of oral treatment with Cpd 19, administered at 100 mpk. Theseparameters are compared with those obtained with control animals(untreated): the difference measured provides evidence of thehypolipemic effect of the compounds according to the invention.

FIG. 11—PPARδ Activating Properties of the Compounds According to theInvention

The stimulating effects of the compounds according to the invention onlipid and carbohydrate metabolism and on energy expenditure in skeletalmuscle were evaluated by measuring the expression of PDK4 (FIG. 11 a),CPT1b (FIG. 11 b), and UCP2 (FIG. 11 c) in murine myocytes treated for24 hours with Cpd 7 or Cpd 24 at different concentrations (0.1, 1, 10 μMand 0.2, 2 and 20 μM respectively). Expression of these genes in thiscell type is a direct consequence of activation of PPARδ by thecompounds according to the invention. As expression of the genes isincreased, the effect of the compound according to the invention asactivator of PPARδ and therefore the stimulating effect on metabolism inmuscle cells increase. The levels of expression shown were normalizedrelative to the level of expression of the 36B4 reference gene.

FIG. 12—PPARγ Activating Properties of the Compounds According to theInvention

The stimulating effects of Cpd 19, Cpd 24 and Cpd36 on adipogenesis wereevaluated by measuring the accumulation of TG (FIGS. 12 a and 12 c) andthe secretion of adiponectin (FIGS. 12 b and 12 d) in a model in vitroof murine pre-adipocytes. After 9 days of treatment with the compoundsin dose response from 30 nM to 30 μM, the levels were compared withthose measured in untreated cells: as the concentrations of TG and ofadiponectin are increased, the greater the adipogenic and thereforePPARγ activating character of the compounds. The activity of thecompounds according to the invention is also compared with the effectsof a reference PPARγ agonist molecule (rosiglitazone). As theaccumulation of triglycerides and secretion of adiponectin areincreased, the greater the effect of the compound according to theinvention as activator of PPARγ and therefore stimulator of metabolismin adipocyte cells.

EXAMPLES Example 1 General Protocols

The compounds of the invention are prepared according to the generalmethods and general protocols of synthesis SA to SY given below. Thecompounds according to the invention and the corresponding reactionintermediates were characterized structurally by ¹H NMR (300 MHz; CDCl₃,CDCl₃+D₂O, or DMSO-d₆, the last mentioned condition notably for thecompounds according to the invention; δ in ppm).

Protocol SA:

The appropriate ketone (acetophenone for Ex. 2-1;4-trifluoroacetophenone for Ex. 2-2; 2-phenylacetophenone for Ex. 2-3;2-acetylfuran for Ex. 2-5; para-acetylbiphenyl for Example 2-6;3-trifluoromethylacetophenone 2.7) is dissolved in dimethyl acetal ofN,N-dimethylformamide (1.2 to 1.5 eq.). The reaction mixture is stirredunder reflux. The estimated reaction time varies between 24 and 48hours. Satisfactory results were obtained in 24 hours.

Protocol SB:

Prop-2-en-1-one from the preceding stage (see Examples 2-1, 2-2, 2-5,2-6, and 2-7) is dissolved in methanol (0.3 to 1.5 mol/L). The reactionmixture is stirred under reflux. The estimated reaction time variesbetween 18 and 48 hours. Satisfactory results were obtained in 18 hours.

Protocol SC:

The methyl ester from the preceding stage (see Examples 2-1, 2-2, 2-5,2-6, 2-7) is dissolved in toluene (0.15 to 0.5 mol/L), then acetic acid(1 to 1.5 eq.) is added. The mixture is stirred under reflux. Theestimated reaction time varies between 12 and 48 hours. Satisfactoryresults were obtained in 18 hours. After it reaches room temperature,the reaction mixture is cooled to 0° C. and the precipitate formed isfiltered and then washed with acetone.

Protocol SD:

The aminopropenone from the preceding stage, cyanoacetamide (1.1 eq.)and methanol (2 eq.) are dissolved in N,N-dimethylformamide (0.3 mol/L).This solution is added to a suspension of NaH (2 eq.) inN,N-dimethylformamide (3 mol/L). The whole is stirred at 95° C. for 18hours.

Protocol SE:

The pyridinone from the preceding stage (Ex. 3-9 for Ex. 3-10; Ex. 3-19for Ex. 3-20) and N-bromosuccinimide (1 to 1.1 eq.) are dissolved inN,N-dimethylformamide (0.1 to 0.4 mol/L). The reaction mixture isstirred under reflux. For a yield of at least 30-80%, the estimatedreaction time varies between 4 and 16 hours. Satisfactory results wereobtained in 4 hours. After returning to room temperature, theprecipitate formed is drained and washed with water and/or heptane.

Protocol SF:

2-oxo-1,2-dihydropyridine (Ex. 2-1 for Ex. 3-1 to 3-4, 3-24, 3-25; Ex.2-2 for Ex. 3-7; Ex. 2-4 for Ex. 3-12; Ex. 2-5 for Ex. 3-13; Ex. 2-6 forEx. 3-15; Ex. 2-7 for Ex. 3-16; 3-18; 2-hydroxynicotinic acid for Ex.3-9) is dissolved in toluene (0.06 to 0.4 mol/L), then silver oxide (1to 1.2 eq.) and the halogenated derivative (for example, 1 to 1.2 eq.;methyl iodide for Ex. 3-1, 3-7, 3-9, 3-12, 3-15, 3-16, 3-19, 5-5; ethyliodide for Ex. 3-24; isopropyl iodide for Ex. 3-25; tert-butyl bromidefor Ex. 3-2; 1-iodohexane for Ex. 3-3; iodocyclohexane for Ex. 3-4) areadded successively. The reaction mixture is stirred under reflux at atemperature which varies between 50° C. and 70° C., and the salts areremoved by filtration. For a yield of at least 40-80% after purificationaccording to purification protocol PA, the estimated reaction timevaries between 1 and 48 hours. Satisfactory results were obtained in 16hours. The reaction can advantageously be carried out under reflux ofacetonitrile to improve the solubility of the reaction mixture.

Protocol SG:

2-oxo-1,2-dihydropyridine (Ex. 2-1 for Ex. 3-5) is dissolved inphosphoryl trichloride (10 eq.) in the presence of a catalytic amount ofN,N-dimethylformamide. The reaction mixture is stirred under reflux for16 hours.

Protocol SH:

Halopyridine (Ex. 3-5 for Ex. 3-8, 3-14) is dissolved in acetonitrile(0.06 to 0.4 mol/L) and potassium carbonate (2 to 3 eq.) is added. Thethiol (for example 1.2 to 3 eq.; thiophenol for Ex. 3-8; ethanethiol forEx. 3-14) is added dropwise and the whole is stirred under reflux. For ayield of at least 80%, the estimated reaction time varies between 18 and48 hours. Satisfactory results were obtained in 18 hours.

Protocol SI:

The intermediate (0.15 mol/L; Ex. 3-1 for Ex. 3-11; Ex. 3-10 for Ex.3-17, Ex. 3-18, Ex. 3-22, Ex. 3-23; Ex. 3-20 for 3-21), potassiumcarbonate (3 eq.) and water (11 eq.) are dissolved inN,N-dimethylformamide under inert atmosphere. Palladium acetate (0.1eq.) is added, then the solution of boronic acid (phenylboronic acid forEx. 3-11 and 3-21; 4-trifluoromethyllboronic acid for Ex. 3-17;3-trifluoromethylphenylboronic acid for Ex. 3-18; 4-chlorophenylboronicacid for Ex. 3-22; naphthalen-2-ylboronic acid for Ex. 3-23) inN,N-dimethylformamide (1.5 eq., 1 mol/L) is added dropwise. Theestimated reaction time varies between 16 and 48 hours. The reactionmixture is stirred under inert atmosphere at room temperature.

Protocol SJ:

The ester of 2-alkoxy-1,2-dihydropyridine (Ex. 3-1 for Ex. 4-1; Ex. 3-2for Ex. 4-2; Ex. 3-3 for Ex. 4-3; Ex. 3-4 for Ex. 4-4; Ex. 3-6 for Ex.4-5; Ex. 3-7 for Ex. 4-6; Ex. 3-8 for Ex. 4-7; Ex. 3-11 for Ex. 4-8; Ex.3-12 for Ex. 4-9; Ex. 3-13 for Ex. 4-10; Ex. 3-14 for Ex. 4-12; Ex. 3-for Ex. 4-; Ex. 3-15 for Ex. 4-13; Ex. 3-16 for Ex. 4-14; Ex. 3-17 forEx. 4-17; Ex. 3-18 for Ex. 4-18; Ex. 3-21 for Ex. 4-19; Ex. 3-22 for Ex.4-20; Ex. 3-23 for Ex. 4-21; Ex. 3-24 for Ex. 4-22; Ex. 3-25 for Ex.4-23) is dissolved in tetrahydrofuran (0.05 to 1.1 mol/L) and thesolution is cooled to 0° C. Aluminum lithium hydride (1 to 2 eq.) isadded in portions and the whole is stirred at room temperature. Thereaction mixture is treated with water (2.5 eq.), 15% soda (17 eq.),then diluted with water (7.5 eq.) and stirring is continued. Theestimated reaction time varies between 1 and 24 hours.

Protocol SK:

Pyridine carboxaldehyde (Ex. 5-1 for Ex. 4-11) is dissolved intetrahydrofuran (0.45 mol/L) and the solution is cooled to −78° C. Asolution of ethylmagnesium bromide (3.4 eq., 2M) is added dropwise. Thewhole is stirred for 18 hours at room temperature.

Protocol SL:

Hydroxymethylpyridine (Ex. 4-1 for Ex. 4-15) and triethylamine (1.5 eq.)are dissolved in tetrahydrofuran (1 mol/L), then paratoluene sulfonylchloride (1.5 eq.) is added. The whole is stirred under reflux for 16hours.

Protocol SM:

Hydroxymethylpyridine (Ex. 4-1 for Ex. 4-16) is dissolved indichloromethane (0.2 mol/L), then the solution is cooled to 0° C.Phosphorus tribromide (1 eq.) is added. The whole is stirred at 0° C.After 0.2 hours, the reaction mixture is poured onto crushed ice andthen extracted with dichloromethane.

Protocol SN:

Hydroxymethylpyridine (Ex. 4-1 for Ex. 5-1; Ex. 4-6 for Ex. 5-3; Ex. 4-8for Ex. 5-4; Ex. 4-9 for Ex. 5-6; Ex. 4-10 for Ex. 5-7; Ex. 4-11 for Ex.5-8; Ex. 4-12 for Ex. 5-9; Ex. 4-13 for Ex. 5-10; Ex. 4-14 for Ex. 5-11;Ex. 4.17 for Ex. 5-12; Ex. 4-18 for Ex. 5-13; Ex. 4-19 for Ex. 5-14; Ex.4-20 for Ex. 5-15; Ex. 4-21 for Ex. 5-16; Ex. 4-22 for Ex. 5-17; Ex.4-23 for Ex. 5-18) is dissolved in dichloromethane (0.06 to 0.5 mol/L),then pyridinium chlorochromate (PCC; 1.2 to 2 eq.) is added. Thereaction mixture is stirred at room temperature. The estimated reactiontime varies between 2 and 48 hours.

Protocol SO:

Hydroxymethylpyridine (Ex. 4-2 for Ex. 5-2) is dissolved indichloromethane (1.5 mol/L), then the solution is cooled to 0° C.Dess-Martin reagent (1.1 eq.) is added dropwise and the whole is stirredat 0° C.

Protocol SP:

1,2-Dihydropyridine-carbonitrile (Ex. 2-3 for Ex. 5-5) is dissolved informic acid (1.1 mol/L) and Raney nickel (50 M.%) is added (1.5 eq.).The whole is stirred for 2 hours under reflux before returning to roomtemperature.

Protocol SQ:

Phenol (4-benzyloxyphenol for Ex. 6-1 to 6-5; 3-nitrophenol for Ex.6-12, 6-13; 4-nitrophenol for Ex. 6-6, 6-11; 4-nitro-2,6-dimethylphenolfor Ex. 6-20), thiophenol (4-aminothiophenol for Ex. 6-10, 6-14, 6-16 to6-19), aniline (4-hydroxy-10-tertiobutoxycarbonylaniline for Ex. 6-7,6-8, 6-9), or acid (2,6-dimethoxynicotinic acid for Ex. 3-19) isdissolved in the appropriate solvent (0.2 to 1.2 mol/L) then thehalogenated derivative or the tosylate (1.2 to 3 eq.; bromodifluoroethylacetate for Ex. 6-18; methyl iodide for Ex. 3-19; ethyl2-bromopropanoate for Ex. 6-3.6-7; ethyl bromoisobutyrate for Ex. 6-1,6-9, 6-10; tert-butyl bromoisobutyrate for Ex. 6-2, 6-5, 6-11, 6-12,6-16; tert-butyl bromoacetate for Ex. 6-13, 6-14; bromoethyl acetate forEx. 6-4, 6-8, 6-17, 6-20; tert-butyl bromoacetate for Ex. 6-6;2-bromo-2-phenylethyl acetate for Ex. 6-19) and potassium carbonate (2.5to 6 eq.) are added. The reaction mixture is stirred vigorously at asuitable temperature and, if necessary, under reflux of acetonitrile,N,N-dimethylformamide, acetonitrile of anacetonitrile/N,N-dimethylformamide mixture (6%), or in the presence oftetrabutylammonium bromide (0.3 eq.). For the compounds according to theinvention, the phenol, the thiophenol, the aniline, or the acid wasprepared in Example 6, and the halogenated derivative or the tosylatewas prepared in Example 4 or 5. The estimated reaction time variesbetween 0.1 and 48 hours and the reaction mixture is cooled to roomtemperature.

Protocol SR:

The ester from the preceding stage is dissolved in the appropriatesolvent (0.3 to 1.2 mol/L of methanol, ethanol, dichloromethane, ormethanol/dichloromethane mixture 1/1 or 2/1), then palladium on charcoal(10 wt. %) is added in catalytic amounts. The whole is stirred, under ahydrogen atmosphere at a suitable pressure. The estimated reaction timevaries between 4 and 120 hours of stirring at room temperature. Thecatalyst is removed by filtration.

Protocol SS:

The protected amine (3-(4-aminophenyl)propanoic acid for Ex. 6-15) isdissolved in ethanol (0.3 to 0.6 mol/L), then an ethanolic solution ofhydrochloric acid is added (2 eq.). The reaction mixture is stirred atroom temperature. The estimated reaction time varies between 2 and 16hours.

Protocol ST:

Triethylphosphonacetate (0.5 mol, L) is added dropwise to a suspensionof sodium hydride (1 eq.) in tetrahydrofuran at 0° C. After stirring for30 min at room temperature, the carbonylated derivative (1 eq.;4-nitrobenzophenone for Ex. 6-21; 4-nitroacetophenone for Ex. 6-24;3-methoxy-4-nitrobenzaldehyde for Ex. 6-23;2-methoxy-4-nitrobenzaldehyde for Ex. 6-22) is added and the reactionmixture is refluxed for 16 hours.

Protocol SU:

The ester from the preceding stage is dissolved in ethanol (0.03 to 1mol/L), then a 1N or 2N solution of soda (1 to 84 eq., preferably from 2to 20 eq.) is added. The whole is stirred at room temperature. For ayield of at least 30-85% after purification according to one of thealternatives presented in example 2, the estimated reaction time variesbetween 1 and 96 hours. Satisfactory results were obtained in 16 hours.If necessary, tetrahydrofuran can advantageously be added to improve thesolubility of the reaction mixture.

Protocol SV:

The phenol (0.1 to 0.9 mol/L) and triphenylphosphine (1.05 eq.) aredissolved in tetrahydrofuran under inert atmosphere. Diisopropylazodicarboxylate (1.05 eq.) and alcohol solution in tetrahydrofuran(1.05 eq., 0.1 to 0.9 mol/L) are added dropwise successively. The wholeis stirred at room temperature. For a yield of at least 30-80%, theestimated reaction time varies between 16 and 72 hours. Satisfactoryresults were obtained in 16 hours. If necessary, dichloromethane can beused advantageously to improve the solubility of the reaction mixture;use of a microwave (for example 0.1 hour at 50° C.) can greatly improvethe performance of the reaction.

Protocol SW:

The tert-butyl ester from the preceding stage is dissolved indichloromethane (0.08 to 0.2 mol/L), and trifluoroacetic acid (10 to 72eq., preferably 10 eq.) is added. Stirring is maintained at roomtemperature. The reaction is carried out at room temperature withstirring. The precipitate is filtered, taken up in water (0.2 L/mol) andtreated with 2N soda solution (3 eq.) for 0.5 hours. The whole isacidified with a 1N solution of citric acid, stirring vigorously, andthen filtered. For a yield of at least 30-80%, the estimated reactiontime varies between 16 and 24 hours. Satisfactory results were obtainedin 16 hours. The reaction mixture can be treated, while stirringvigorously, with a 10% solution of potassium carbonate for 0.5 hours(pH=8-9) before being acidified.

Protocol SX:

The aldehyde and the aniline (1 to 1.5 eq.) are dissolved indichloromethane (0.1 to 0.4 mo/L), under inert atmosphere. The reactionmixture is stirred at room temperature for 1 hour. Sodiumtriacetoxyborohydride (1.2 to 1.5 eq.) is added in portions, then thewhole is stirred vigorously at room temperature. When the anilinerequired is available in its hydrochloride form, it is first salted-outby basic treatment. For a yield of at least 40-85% after purificationaccording to one of the alternatives presented in example 2, theestimated reaction time varies between 2.5 and 72 hours. Satisfactoryresults were obtained in 16 hours. Working with an anhydrous solventand/or in the presence of a molecular sieve 3A can greatly improve theperformance of the reaction.

Protocol SY:

The ketone and the aniline (1.2 eq.) are dissolved in toluene (0.03mo/L), in the presence of paratoluenesulfonic acid (1 eq.) and molecularsieve 3 Å, in a Dean-Stark apparatus. The reaction mixture is stirred at110° C. for 16 hours. After cooling, the insoluble matter is filteredand the filtrate is concentrated under reduced pressure. The evaporationresidue is taken up in dichloromethane. Sodium triacetoxyborohydride(1.5 eq.) is added in portions, then the whole is stirred vigorously atroom temperature in the presence of molecular sieve 3 Å for 48 hours.When the aniline required is available in its hydrochloride form, it isfirst salted-out by basic treatment.

The raw reaction products obtained can be purified following one or moreof the general purification protocols PA to PE. For this purpose,conventional preliminary steps of hydrolysis (without dilution, or withdilution, for example, with ethyl acetate) or washing (neutral, acid orbasic, for example with water, saturated solution of sodium chloride, 1Nsolution of citric acid, saturated solution of ammonium chloride, 10%solution of potassium carbonate, 1N solution of sodium hydroxide), thenextraction of the reaction mixture with a suitable solvent (diethylether or dichloromethane, for example), drying of the organic phases(for example, over magnesium sulfate), concentration (notably of thereaction mixture, notably by evaporation under reduced pressure), and/orremoval of insoluble matter can advantageously be carried out (the saltsare removed by filtration, for example).

In the case of protocol PA, silica gel flash chromatography (40-63 μm)was performed with various conditions of elution (mobile phase), assummarized in Table 1-1.

TABLE 1-1 Mobile Phase Examples dichloromethane/ Stg. 1 for Ex. 2-5,4-1, 4-7, 5-5; Cpd 33; methanol or (9/1 to 98/2) Stg. 2 for Cpd 1, Cpd8, Cpd 10, Cpd 11, Cpd 15, Cpd 21, Cpd 22, Cpd 24, Cpd 28, Cpd 29, Cpd32-36, Cpd 38-48, Cpd 50, Cpd 51, Cpd 53, Cpd 54 Stg. 3 for 2-7,dichloromethane/ Stg. 2 for 5-5 cyclohexane (8/2) dichloromethane/ethylStg. 1 for Ex. 3-3, 3-4, 3-12, 5-1, 5-12, 5-13, 5-15, 5-175-6, 5-18, andacetate or 6-5; Cpd 3, Cpd 6, Cpd 7, Cpd 13-18, Cpd 32, Cpd 34, Cpd 36,Cpd cyclohexane/ethyl acetate 38, Cpd 42, Cpd 43, Cpd 46-48 (95/5 or98/2) Stg. 2 for Cpd 15 dichloromethane/ethyl Stg. 1 for Ex. 2-3, 3-2,3-5, 3-7, 3-8, 3-11, 3-13, 3-14, 3.22, 3-23, 3- acetate or cyclohexane/24, 4-5, 4-9, 4-11, 4-21, 5-2, 5-4, 5-7, 5-8, 5-9, 5-14, 5-16, 6-1, 6-3,6- ethyl acetate (9/1 or 4, 6-12, 6-14, 6-18, 6-22; Cpd 1, Cpd 2, Cpd 4,Cpd 5, Cpd 8, Cpd 9, 85/15) Cpd 10, Cpd 11, Cpd 12, Cpd 16, Cpd 19-26,Cpd 30, Cpd 31, Cpd 39, Cpd 40, Cpd 41, Cpd 44, Cpd 45, Cpd 49-54 Stg. 2for Ex. 6-3, 6-12 dichloromethane/ethyl Stg. 1 for Ex. 3-1, 3-9, 3-15,3-16, 3-19, 3-25, 4-2, 4-6, 4-10, 4-12, 4- acetate or cyclohexane/ 13,4.14, 4-15, 4-19, 5-3, 5-10, 5-11, 6-10, 6-11, 6-13, 6-16, 6-17, 6-ethyl acetate (7/3, 8/2, or 19, 6-21, 6-23, 6-24; Cpd 27, Cpd 28, Cpd29, Cpd 35; 6/4) Stg. 2 for Ex. 6-5 6-21, 6-24

In the case of protocol PB, silica gel chromatography is performed bypreparative HPLC (lichrospher, Merck; RP18 12 μm 100A, column: 25*250mm; Stg. 2 for Cpd 5, Cpd 13, Cpd 14, Cpd 17, Cpd 18, Cpd 20, Cpd 23,Cpd 52; Stg. 1 for Cpd 37).

In the case of protocol PC, precipitation is performed in a mixture ofsolvents which are selected from the usual solvents by a person skilledin the art such as notably dichloromethane, heptane, cyclohexane,toluene, for example dichloromethane/heptane 4/6 (Stg. 1 for Ex. 2-1,2-2, 2-6; Stg. 2 for Cpd 12, Cpd 16, Cpd 19, Cpd 22, Cpd 27, Cpd 30, Cpd31, Cpd 49; Stg. 3 for Cpd 46, Cpd 47, Cpd 48, Cpd 51, Cpd 53),dichloromethane/toluene 4/6 (Stg. 2 for Ex. 2-5), ordichloromethane/cyclohexane 4/6 (Stg. 3 for Cpd 45, Cpd 54).

In the case of protocol PD, (re)crystallization is performed in asolvent selected from the usual solvents by a person skilled in the artsuch as isopropanol (Stg. 2 for Cpd 9), ethanol (Stg. 2 for Ex. 2-1, Cpd25), acetone (Stg. 2 for Ex. 2-2), methanol (Stg. 2 for Ex. 2-6, Cpd 3,Cpd 6, Cpd 7), petroleum ether (Stg. 1 for Ex. 6-2, 6-13),dichloromethane, heptane (Stg. 1 for Ex. 6-11, 6-20), cyclohexane (Stg.1 for Ex. 6-6, 6-7, 6-9), or a mixture for example withdichloromethane/heptane (Cpd 15, Cpd 21, Cpd 24, Cpd 28, Cpd 29, Cpd 32,Cpd 42, Cpd 43, Cpd 44)

In the case of protocol PE, the product that precipitates is filtered atthe end of the reaction. The estimated reaction time varies between 12and 24 hours. After the reaction mixture has cooled to 0° C., hydrolysisor acid hydrolysis of the reaction mixture (Stg. 3 for Ex. 2-1, 2.2, 2-5to 2-7, Stg. 3 for Ex. 2-3, 2-4; Cpd 2, Cpd 4, Cpd 26; Stg. 1 for Ex.3-20) or a sequence of basic hydrolysis/filtration/trituration of thefilter cake in acid aqueous medium (for example in ethanol; Stg. 2 forEx. 6-7, 6-8, 6-9; Stg. 1 for Ex. 6-15) is performed.

Example 2 Synthesis of the Intermediates of the2-Oxo-1,2-Dihydropyridine Type According to the Invention

The synthesis of these intermediates (FIG. 2) requires 2 or 3 stages, assummarized in Table 2-1:

TABLE 2-1 Ex. No. and type of Stage (Protocol) Details 2-1 1:Preparation of 3-dimethylamino-1- Yield: 92%. Appearance: yellow solid.phenylprop-2-en-1-one (Protocol SA and ¹H NMR: 2.93-3.14 (m, 6H); 5.73(d, 1H, PC) J = 12.4 Hz); 7.38-7.49 (m, 3H); 7.82 (d, 1H, J = 12.4 Hz);7.89 (d, 2H, J = 7.9 Hz). 2: Preparation of methyl 2-carbamoyl-5- Yield:63% dimethylamino-5-phenylpentane-2,4- dienoate (Protocol SB and PD) 3:Obtaining methyl 2-oxo-6-phenyl-1,2- Yield: 66%. Appearance: yellowsolid. dihydropyridine-3-carboxylate (Protocol ¹H NMR: 3.77 (s, 3H);6.79 (d, 1H, J = 7.6 Hz); SC and PE) 7.51-7.53 (m, 3H); 7.82-7.85 (m,2H); 8.14 (d, 1H, J = 7.6 Hz). 2-2 1: Preparation of3-dimethylamino-1-(4- Yield: 81%. Appearance: yellow solid.trifluoromethylphenyl)prop-2-en-1-one ¹H NMR: 2.94 (s, 3H); 3.17 (s,3H); 5.69 (d, 1H, (Protocol SA and PC) J = 12.3 Hz); 7.66 (d, 2H, J =8.2 Hz); 7.83 (d, 1H, J = 12.3 Hz); 7.97 (d, 2H, J = 8.2 Hz). 2:Preparation of methyl 2-carbamoyl-5- Yield: 37%. Appearance: yellowsolid. dimethylamino-5-(4- trifluoromethylphenyl)pentane-2,4- dienoate(Protocol SB and PD) 3: Obtaining methyl 2-oxo-6-(4- Yield: 38%.Appearance: yellow solid. (trifluoromethyl)phenyl)-1,2- ¹H NMR: 4.02 (s,3H); 7.35 (d, 1H, J = 8.3 Hz); dihydropyridine-3-carboxylate (Protocol7.75 (d, 2H, J = 8.3 Hz); 8.17 (d, 2H, J = 8.3 Hz); SC and PE) 8.31 (d,1H, J = 8.3 Hz). 2-3 1: Preparation of 1,2-diphenylprop-2-en- Yield:68%. Appearance: yellow solid. 1-one (Protocol SA and PE) ¹H NMR: 2.72(s, 6H); 7.09-7.46 (m, 11H). 2: Obtaining 2-oxo-5,6-diphenyl-1,2- Yield:73%. Appearance: white solid. dihydropyridine-3-carbonitrile (Protocol¹H NMR: 7.03-7.06 (m, 2H); 7.19-7.40 (m, 8H); SD and PE) 8.23 (s, 1H);12.76 (s, 1H). 2-4 Methyl 5-bromo-2-oxo-6-phenyl-1,2- Yield: 37%.Appearance: white solid. dihydropyridine-3-carboxylate (Protocol ¹H NMR:3.79 (s, 3H); 7.50-7.57 (m, 5H); 8.23 SE and PE) (s, 1H); 12.49 (s(I),1H). 2.5 1: Preparation of 3-dimethylamino-1- Yield: 69%. Appearance:yellow solid. furyl-prop-2-en-1-one (Protocol SA and ¹H NMR: 2.93 (s,3H); 3.14 (s, 3H); 5.68 (d, 1H, PA) J = 12.6 Hz); 6.48 (m, 1H); 7.06 (m,1H); 7.49 (m, 1H); 7.80 (d, 1H, J = 12.6 Hz). 2: Preparation of methyl2-carbamoyl-5- Yield: 24%. Appearance: yellow solid.dimethylamino-5-furyl-pentane-2,4- dienoate (Protocol SB and PC) 3:Obtaining methyl 6-furyl-2-oxo-1,2- Yield: 47%. Appearance: yellowsolid. dihydropyridine-3-carboxylate (Protocol ¹H NMR: 3.98 (s, 3H);6.59-6.60 (m, 1H); 7.15 SC and PE) (m, 1H); 7.40 (m, 1H); 7.59 (d, 1H, J= 1.1 Hz); 8.26 (d, 1H, J = 7.9 Hz). 2-6 1: Preparation of3-dimethylamino-1- Yield: 40%. Appearance: yellow solid.parabiphenylprop-2-en-1-one (Protocol ¹H NMR: 2.97-3.16 (m, 6H); 5.79(d, 1H, SA and PC) J = 12.3 Hz); 7.35-7.40 (m, 1H); 7.46-7.49 (m, 2H);7.63-7.67 (m, 4H); 7.85 (d, 1H, J = 12.3 Hz); 7.89 (d, 2H, J = 8.2 Hz).2: Preparation of methyl 2-carbamoyl- Yield: 43%. Appearance: yellowsolid. 5-dimethylamino-5-(parabiphenyl) pentane-2,4-dienoate (ProtocolSB and PD) 3: Obtaining methyl 2-oxo-6- Yield: 59%. Appearance: yellowsolid. parabiphenyl-1,2-dihydropyridine-3- ¹H NMR: 4.00 (s, 3H);7.17-7.24 (m, 1H); 7.38- carboxylate. (Protocol SC and PE) 7.42 (m, 1H);7.46-7.51 (m, 2H); 7.66 (d, 2H, J = 7.3 Hz); 7.74 (d, 2H, J = 8.5 Hz);8.09 (d, 2H, J = 8.5 Hz); 8.29 (d, 1H, J = 7.9 Hz). 2-7 1: Preparationof 3-dimethylamino-1- Yield: 53%. Appearance: brown oil.(3-trifluoromethylphenyl)prop-2-en-1- ¹H NMR: 2.88 (s, 3H); 3.10 (s,3H); 5.64 (d, 1H, one (Protocol SA and PA) J = 12.3 Hz); 7.48 (m, 1H);7.64 (d, 1H, J = 7.9 Hz); 7.80 (d, 1H, J = 12.3 Hz); 8.03 (d, 1H, J =7.6 Hz); 8.11 (s, 1H). 2: Preparation of methyl 2-carbamoyl- Yield: 23%.Appearance: yellow solid. 5-dimethylamino-5-(3-trifluoromethylphenyl)-pentane-2,4- dienoate (Protocol SB and PA) 3:Obtaining methyl 2-oxo-6-(4- Yield: 58%. Appearance: beige solid.(trifluoromethyl)phenyl)-1,2- ¹H NMR: 4.02 (s, 3H); 7.36 (d, 1H, J = 8.2Hz); dihydropyridine-3-carboxylate 7.62 (t, 1H, J = 7.9 Hz); 7.73 (d,1H, J = 7.9 Hz); (Protocol SC and PE) 8.25 (d, 1H, J = 7.9 Hz);8.30-8.32 (m, 2H).

Example 3 Synthesis of the Intermediates of the Alkoxy, Alkylthio,Alkylamino, Halo-Pyridine Type According to the Invention

Synthesis of the intermediates in FIG. 3 a is summarized in Table 3-1.

TABLE 3-1 Ex. Intermediates (Protocols) Details 3-1 Methyl2-methoxy-6-phenyl- Yield: 73%. Appearance: colorless oil.pyridine-3-carboxylate (Protocol ¹H NMR: 3.94 (s, 3H); 4.19 (s, 3H);7.42-7.54 (m, 4H); SF and PA) 8.11 (dd, 2H, J = 1.7 Hz J = 7.9 Hz); 8.27(d, 1H, J = 7.9 Hz). 3-2 Methyl 2-tert-butoxy-6-phenyl- Yield: 56%.Appearance: white solid. pyridine-3-carboxylate (Protocol ¹H NMR: 1.74(s, 9H); 3.91 (s, 3H); 7.38 (d, 1H, J = 7.9 SF and PA) Hz); 7.45-7.52(m, 3H); 8.06 (m, 2H); 8.19 (d, 1H, J = 7.9 Hz). 3-3 Methyl2-hexyloxy-6-phenyl- Yield: 80%. Appearance: colorless oil.pyridine-3-carboxylate (Protocol ¹H NMR: 0.93 (t, 3H, J = 6.7 Hz);1.34-1.42 (m, 4H); 1.50- SF and PA) 1.57 (m, 2H); 1.85-1.94 (m, 2H);3.93 (s, 3H); 4.58 (t, 2H, J = 6.7 Hz); 7.41 (d, 1H, J = 7.9 Hz);7.43-7.53 (m, 3H); 8.09 (dd, 2H, J = 1.9 Hz, J = 8.1 Hz); 8.26 (d, 1H, J= 7.9 Hz). 3-4 Methyl 2-cyclohexyloxy-6- Yield: 12%. Appearance:colorless oil. phenyl-pyridine-3-carboxylate ¹H NMR: 1.46-2.09 (m, 10H);3.92 (s, 3H); 5.41-5.46 (Protocol SF and PA) (m, 1H); 7.38 (d, 1H, J =7.9 Hz); 7.45-7.53 (m, 3H); 8.06 (dd, 2H, J = 1.9 Hz, J = 8.2 Hz); 8.24(d, 1H, J = 7.9 Hz). 3-7 Methyl 2-methoxy-6-(4- Yield: 67%. Appearance:white solid. (trifluoromethyl)phenyl)-pyridine- ¹H NMR: 3.94 (s, 3H);4.18 (s, 3H); 7.46 (d, 1H, 3-carboxylate (Protocol SF and J = 7.6 Hz);7.75 (d, 2H, J = 8.2 Hz); 8.21 (d, 2H, PA) J = 8.2 Hz); 8.29 (d, 1H, J =7.6 Hz). 3-9 Methyl 2-methoxy-pyridine-3- Yield: 38%. Appearance:colorless oil. carboxylate (Protocol SE and ¹H NMR: 3.90 (s, 3H); 4.04(s, 3H); 6.95 (dd, 1H, PA) J = 4.8 Hz, J = 7.5 Hz); 8.15 (dd, 1H, J =2.0 Hz J = 7.5 Hz); 8.31 (dd, 1H, J = 2.0 Hz J = 4.8 Hz). 3-12 Methyl5-bromo-2-methoxy-6- Yield: 48%. Appearance: white solid.phenyl-pyridine-3-carboxylate ¹H NMR: 3.94 (s, 3H); 4.07 (s, 3H);7.45-7.50 (m, 3H); (Protocol SF and PA) 7.78-7.82 (m, 2H); 8.43 (s, 1H).3-13 Methyl 2-methoxy-6-furyl- Yield: 70%. Appearance: white solid.pyridine-3-carboxylate (Protocol ¹H NMR: 3.91 (s, 3H); 4.11 (s, 3H);6.55-6.57 (m, 1H); SF and PA) 7.15 (d, 1H, J = 3.5 Hz); 7.33 (d, 1H, J =7.9 Hz); 7.56 (m, 1H); 8.23 (d, 1H, J = 7.9 Hz). 3-15 Methyl2-methoxy-6- Appearance: white solid. (parabiphenyl)-pyridine-3- ¹H NMR:3.94 (s, 3H); 4.20 (s, 3H); 7.34-7.40 (m, 1H); carboxylate (Protocol SFand 7.46-7.51 (m, 3H); 7.67 (d, 2H, J = 7.6 Hz); 7.73 (d, 2H, PA) J =8.2 Hz); 8.19 (d, 2H, J = 8.2 Hz); 8.28 (d, 1H, J = 7.6 Hz). 3-16 Methyl2-methoxy-6-(3- Yield: 30%. Appearance: white solid(trifluoromethyl)phenyl)-pyridine- ¹H NMR: 3.93 (s, 3H); 4.17 (s, 3H);7.43 (d, 1H, 3-carboxylate (Protocol SF and J = 7.7 Hz); 7.59 (m, 1H);7.69 (d, 1H, J = 7.9 Hz); 8.24- PA) 8.26 (m, 1H); 8.27 (d, 1H, J = 7.7Hz); 8.33 (s, 1H). 3-24 Methyl 2-ethoxy-6-phenyl- Yield: 86%.Appearance: white solid. pyridine-3-carboxylate (Protocol ¹H NMR: 1.51(t, 3H, J = 7.0 Hz); 3.92 (s, 3H); 4.65 (q, SF and PA) 2H, J = 7.0 Hz);7.40 (d, 1H, J = 7.9 Hz); 7.43-7.52 (m, 3H); 8.08 (dd, 2H, J = 2.1 Hz J= 8.2 Hz); 8.24 (d, 1H, J = 7.9 Hz). 3-25 Methyl 2-isopropoxy-6-phenyl-Yield: 74%. Appearance: colorless oil. pyridine-3-carboxylate ¹H NMR:1.47 (s, 3H); 1.49 (s, 3H); 3.91 (s, 3H); 5.58- (Protocol SF and PA)5.66 (m, 1H); 7.37 (d, 1H, J = 7.9 Hz); 7.42-7.52 (m, 3H); 8.07 (dd, 2H,J = 2.0 Hz, J = 8.2 Hz); 8.22 (d, 1H, J = 7.9 Hz).

Introduction of groups in position 5, and notably of groups of the arylor alkyl type, can be performed by coupling of the Suzuki type betweenthe appropriately selected boronic acid precursor and the appropriate5-halopyridine. The intermediates 3-11, 3-17, 3-18, 3-21 to 3-23 wereprepared from 5-bromopyridines 3-10 and 3-20. The synthesis of theseintermediates (FIG. 3 b) is summarized in Table 3-2.

TABLE 3-2 Ex. Intermediate (Protocol) Details 3-10 Methyl5-bromo-2-methoxy- Yield: 33%. Appearance: gray solid.pyridine-3-carboxylate (Protocol SE ¹H NMR: 3.81 (s, 3H); 3.91 (s, 3H);8.24 (d, 1H, and PE) J = 2.3 Hz); 8.50 (d, 1H, J = 2.3 Hz). 3-11 Methyl2-methoxy-5-phenyl- Yield: 71%. Appearance: colorless oil.pyridine-3-carboxylate (Protocol SI ¹H NMR: 3.94 (s, 3H); 4.11 (s, 3H);7.36-7.42 (m, and PA) 1H); 7.45-7.50 (m, 2H); 7.55-7.58 (m, 2H); 8.39(d, 1H, J = 2.6 Hz); 8.55 (d, 1H, J = 2.6 Hz). 3-17 Methyl2-methoxy-5-(4- Yield: 21%. Appearance: white solid.(trifluoromethyl)phenyl)-pyridine-3- ¹H NMR: 3.96 (s, 3H); 4.12 (s, 3H);7.67 (d, 2H, carboxylate (Protocol SI and PA) J = 8.3 Hz); 7.74 (d, 2H,J = 8.3 Hz); 8.40 (d, 1H, J = 2.6 Hz); 8.57 (d, 1H, J = 2.6 Hz). 3-18Methyl 2-methoxy-5-(3- Yield: 30%. Appearance: white solid.(trifluoromethyl)phenyl)-pyridine-3- ¹H NMR: 3.92 (s, 3H); 4.12 (s, 3H);7.57-7.67 (m, carboxylate (Protocol SI and PA) 2H); 7.73-7.75 (m, 1H);7.80 (s, 1H); 8.39 (d, 1H, J = 2.6 Hz); 8.56 (d, 1H, J = 2.6 Hz). 3-19Methyl 2,6-dimethoxy-pyridine-3- Yield: 69%. Appearance: white solid.carboxylate (Protocol SQ and PA) ¹H NMR: 3.86 (s, 3H); 3.98 (s, 3H);4.05 (s, 3H); 6.33 (d, 1H, J = 8.2 Hz); 8.14 (d, 1H, J = 8.2 Hz). 3-20Methyl 5-bromo-2,6-dimethoxy- Yield: 81%. Appearance: white solid.pyridine-3-carboxylate (Protocol SE ¹H NMR: 3.76 (s, 3H); 3.96 (s, 3H);4.01 (s, 3H); and PE) 8.24 (s, 1H). 3-21 Methyl 5-phenyl-2,6-dimethoxy-Yield: 76%. Appearance: white solid. pyridine-3-carboxylate (Protocol SI¹H NMR: 3.88 (s, 3H); 4.03 (s, 3H); 4.11 (s, 3H); and PA) 7.31-7.36 (m,1H); 7.39-7.44 (m, 2H); 7.52-7.55 (m, 2H); 8.26 (s, 1H). 3-22 Methyl5-(4-chlorophenyl)-2- Yield: 97%. Appearance: white solid.methoxy-pyridine-3-carboxylate ¹H NMR: 3.95 (s, 3H); 4.10 (s, 3H); 7.44(d, 2H, (Protocol SI and PA) J = 8.8 Hz); 7.49 (d, 2H, J = 8.8 Hz); 8.35(d, 1H, J = 2.4 Hz); 8.50 (d, 1H, J = 2.4 Hz). 3-23 Methyl5-(naphthalen-2-yl)-2- Yield: 84%. Appearance: white solid.methoxy-pyridine-3-carboxylate ¹H NMR: 3.97 (s, 3H); 4.13 (s, 3H);7.49-7.57 (m, (Protocol SI and PA) 2H); 7.70 (dd, 1H, J = 2.0 Hz J = 8.5Hz); 7.87-7.97 (m, 3H); 8.02 (s, 1H); 8.52 (d, 1H, J = 2.5 Hz); 8.68 (d,1H, J = 2.5 Hz).

Intermediates substituted in position 2 with alkylthio, alkylaminogroups are accessible starting from the corresponding 2-halopyridine.The intermediates 3-6, 3-8 and 3-14 were prepared from 2-chloropyridine3-5 (FIG. 3 c), as summarized in Table 3-3.

TABLE 3-3 Ex. Intermediate (protocols) Details 3-5 Methyl2-chloro-6-phenyl-pyridine- Yield: 83%. Appearance: white solid.3-carboxylate (Protocol SG and ¹H NMR: 3.99 (s, 3H); 7.48-7.53 (m, 3H);7.75 (d, 1H, PA) J = 8.1 Hz); 8.05-8.08 (m, 2H); 8.26 (d, 1H, J = 8.1Hz). 3-6 Methyl 2-(piperidin-1-yl)-6-phenyl- Yield: 95%. Appearance:yellow oil. pyridine-3-carboxylate ¹H NMR: 1.60-1.73 (m, 6H); 3.47-3.49(m, 4H); 3.91 (intermediate 3-5 is dissolved in (s, 3H); 7.18 (d, 1H, J= 7.9 Hz); 7.41-7.49 (m, 3H); piperidine (0.1 mol/L) and the 8.05 (d,1H, J = 7.9 Hz); 8.06 (dd, 2H, J = 1.6 Hz, whole is stirred under refluxfor 16 J = 8.2 Hz). hours; Protocol PA) 3-8 Methyl2-phenylthio-6-phenyl- Yield: quantitative. Appearance: colorless oil.pyridine-3-carboxylate (Protocol ¹H NMR: 4.01 (s, 3H); 7.25-7.35 (m,3H); 7.46-7.53 SH and PA) (m, 4H); 7.60-7.66 (m, 4H); 8.28 (d, 1H, J =8.2 Hz). 3-14 Methyl 2-ethylthio-6-phenyl- Yield: 90%. Appearance: beigesolid. pyridine-3-carboxylate (Protocol ¹H NMR: 1.47 (t, 3H, J = 7.3Hz); 3.34 (q, 2H, J = 7.3 Hz); SH and PA) 3.95 (s, 3H); 7.47-7.54 (m,4H); 8.11-8.14 (m, 2H); 8.28 (d, 1H, J = 8.2 Hz).

Example 4 Synthesis of the Intermediates of the 3-Hydroxymethyl-,3-Halomethyl- and 3-Arylsulfonylmethyl-Pyridine Type According to theInvention

Synthesis of the intermediates in FIG. 4 a is summarized in Table 4-1.

TABLE 4-1 Ex. Intermediate (Protocol) Details 4-1(2-methoxy-6-phenylpyridin-3- Yield: 96%. Appearance: yellow solid.yl)methanol ¹H NMR: 4.12 (s, 3H); 4.71 (s, 2H); 7.36-7.50 (m, 4H);(Protocol SJ and PA) 7.64 (d, 1H, J = 7.3 Hz); 8.06 (m, 2H). 4-2(2-tert-butoxy-6-phenylpyridin- Yield: 91%. Appearance: white solid.3-yl)methanol (Protocol SJ and ¹H NMR: 1.73 (s, 9H); 4.64 (s, 2H); 7.33(d, 1H, PA) J = 7.5 Hz); 7.37-7.50 (m, 3H); 7.58 (d, 1H, J = 7.5 Hz);8.02 (m, 2H). 4-3 (2-hexyloxy-6-phenylpyridin-3- Yield: quantitative.Appearance: white solid. yl)methanol (Protocol SJ) ¹H NMR: 0.92 (t, 3H,J = 6.7 Hz); 1.27-1.53 (m, 6H); 1.80- 1.90 (m, 2H); 4.52 (t, 2H, J = 6.7Hz); 4.70 (d, 2H, J = 6.2 Hz); 7.34 (d, 1H, J = 7.3 Hz); 7.37-7.49 (m,3H); 7.62 (d, 1H, J = 7.6 Hz); 8.02-8.05 (m, 2H). 4-4(2-cyclohexyloxy-6- Yield: 88%. Appearance: clear oil.phenylpyridin-3-yl)methanol ¹H NMR: 1.37-1.69 (m, 6H); 1.79-1.83 (m,2H); 2.05 (m, (Protocol SJ) 2H); 4.68 (d, 2H, J = 6.4 Hz); 5.32-5.38 (m,1H); 7.32 (d, 1H, J = 7.3 Hz); 7.36-7.49 (m, 3H); 7.60 (d, 1H, J = 7.6Hz); 8.01 (m, 2H). 4-5 (6-phenyl-2-(piperidin-1- Yield: 46%. Appearance:white solid. yl)pyridin-3-yl)methanol ¹H NMR: 1.62-1.83 (m, 6H);3.18-3.22 (t, 4H, J = 5.4 Hz); (Protocol SJ and PA) 4.80 (s, 2H); 4.94(s, 1H); 7.36-7.49 (m, 4H); 7.57 (d, 1H, J = 7.9 Hz); 8.04 (m, 2H). 4-6(2-methoxy-6-(4-(trifluoro Yield: 93%. Appearance: white solid.methyl)phenyl)pyridin-3-yl) ¹H NMR: 4.12 (s, 3H); 4.72 (s, 2H); 7.41 (d,1H, methanol (Protocol SJ and PA) J = 7.6 Hz); 7.68-7.73 (m, 3H); 8.16(d, 2H, J = 8.2 Hz). 4-7 (6-phenyl-2- Yield: 39%. Appearance: whitesolid. (phenylthio)pyridin-3-yl) ¹H NMR: 4.84 (s, 2H); 7.31-7.36 (m,3H); 7.38-7.46 (m, methanol (Protocol SJ and PA) 3H); 7.55-7.63 (m, 3H);7.73-7.78 (m, 3H). 4-8 (2-methoxy-5-phenylpyridin-3- Yield:quantitative. Appearance white solid. yl)methanol (Protocol SJ) ¹H NMR:4.05 (s, 3H); 4.73 (s, 2H); 7.34-7.39 (m, 1H); 7.43-7.47 (m, 2H);7.53-7.56 (m, 2H); 7.83 (d, 1H, J = 2.3 Hz); 8.32 (d, 1H, J = 2.3 Hz).4-9 (5-bromo-2-methoxy-6- Yield: 50%. Appearance: white solid.phenylpyridin-3-yl)methanol ¹H NMR: 4.00 (s, 3H); 4.68 (s, 2H);7.42-7.50 (m, 3H); (Protocol SJ and PA) 7.74-7.77 (m, 2H); 7.86 (s, 1H).4-10 (2-methoxy-6-furylpyridin-3- Yield: 78%. Appearance: white solid.yl)methanol (Protocol SJ and ¹H NMR: 2.25 (t, 1H, J = 6.3 Hz); 4.05 (s,3H); 4.66 (d, 2H, PA) J = 6.3 Hz); 6.51-6.53 (m, 1H); 7.01-7.02 (m, 1H);7.29 (d, 1H, J = 7.6 Hz); 7.5-7.51 (m, 1H); 7.60 (d, 1H, J = 7.6 Hz).4-12 (2-(ethylthio)-6-phenylpyridin- Yield: 75%. Appearance: yellow oil.3-yl)methanol (Protocol SJ and ¹H NMR: 1.47 (t, 3H, J = 7.3 Hz); 3.39(q, 2H, J = 7.3 Hz); PA) 4.72 (s, 2H); 7.39-7.51 (m, 4H); 7.67 (d, 1H, J= 7.9 Hz); 8.07 (d, 2H, J = 7.0 Hz). 4-13 (2-methoxy-6 (parabiphenyl)Yield: 59%. Appearance: white solid. pyridin-3-yl)methanol (Protocol ¹HNMR: 2.29 (t, 1H, J = 6.6 Hz); 4.14 (s, 3H); 4.71 (d, 2H, SJ and PA) J =6.6 Hz); 7.36-7.50 (m, 4H); 7.65-7.72 (m, 5H); 8.14 (d, 2H, J = 6.7 Hz).4-14 (2-methoxy-6-(3- Yield: 85%. Appearance: white solid.(trifluoromethyl)phenyl)pyridin- ¹H NMR: 2.26 (t, 1H, J = 6.6 Hz); 4.12(s, 3H); 4.72 (d, 2H, 3-yl)methanol (Protocol SJ and J = 6.6 Hz); 7.41(d, 1H, J = 7.3 Hz); 7.56-7.70 (m, 3H); 8.22 PA) (d, 1H, J = 7.9 Hz);8.31 (s, 1H). 4-17 (2-methoxy-5-(4- Yield: quantitative. Appearance:white solid. (trifluoromethyl)phenyl)pyridin- ¹H NMR: 4.02 (s, 3H); 4.72(d, 2H, J = 5.3 Hz); 7.60 (d, 2H, 3-yl)methanol (Protocol SJ) J = 8.3Hz); 7.67 (d, 2H, J = 8.3 Hz); 7.86 (d, 1H, J = 2.5 Hz); 8.30 (d, 1H, J= 2.5 Hz). 4-18 (2-methoxy-5-(3- Yield: 77%. Appearance: white solid.(trifluoromethyl)phenyl)pyridin- ¹H NMR: 4.05 (s, 3H); 4.74 (s, 2H);7.54-7.63 (m, 2H); 3-yl)methanol (Protocol SJ) 7.71-7.73 (m, 1H); 7.78(s, 1H); 7.85 (d, 1H, J = 2.5 Hz); 8.33 (d, 1H, J = 2.5 Hz). 4-19(2,6-dimethoxy-5- Yield: 77%. Appearance: white solid.phenylpyridin-3-yl)methanol ¹H NMR: 3.98 (s, 3H); 4.04 (s, 3H); 4.65 (s,2H); 7.30- (Protocol SJ and PA) 7.33 (m, 1H); 7.38-7.43 (m, 2H);7.52-7.57 (m, 3H). 4-20 (5-(4-chlorophenyl)-2- Yield: 84%. Appearance:colorless oil. methoxypyridin-3-yl)methanol ¹H NMR: 4.04 (s, 3H); 4.72(d, 2H, J = 6.5 Hz); 7.42 (d, 2H, (Protocol SJ) J = 8.8 Hz); 7.47 (d,2H, J = 8.8 Hz); 7.79 (d, 1H, J = 2.3 Hz); 8.28 (d, 1H, J = 2.3 Hz).4-21 (2-methoxy-5-(naphthalen-2- Yield: 75%. Appearance: white solid.yl)pyridin-3-yl)methanol ¹H NMR: 4.07 (s, 3H); 4.77 (s, 2H); 7.49-7.53(m, 2H); (Protocol SJ and PA) 7.69 (dd, 1H, J = 1.9 Hz, J = 8.5 Hz);7.86-7.99 (m, 5H); 8.45 (d, 1H, J = 2.5 Hz). 4-22(2-ethoxy-6-phenylpyridin-3- Yield: 91%. Appearance: white solid.yl)methanol (Protocol SJ) ¹H NMR: 1.47 (t, 3H, J = 7.2 Hz); 4.59 (q, 2H,J = 7.2 Hz); 4.69 (d, 2H, J = 5.6 Hz); 7.34 (d, 1H, J = 7.6 Hz);7.37-7.49 (m, 3H); 7.62 (d, 1H, J = 7.6 Hz); 8.01-8.05 (m, 2H). 4-23(2-isopropoxy-6-phenylpyridin- Yield: quantitative. Appearance:colorless oil. 3-yl)methanol (Protocol SJ) ¹H NMR: 1.43 (s, 3H); 1.45(s, 3H); 4.67 (d, 2H, J = 6.4 Hz); 5.56-5.64 (m, 1H); 7.32 (d, 1H, J =7.5 Hz); 7.36-7.49 (m, 3H); 7.60 (d, 1H, J = 7.5 Hz); 8.00-8.04 (m, 2H).

Synthesis of the intermediates in FIGS. 4 b, 4 c and 4 d is summarizedin Table 4-2

TABLE 4-2 Ex. Intermediate (Protocol) Details 4-111-(2-methoxy-6-phenylpyridin- Yield: 66%. Appearance: beige solid3-yl)propan-1-ol (Protocol SK ¹H NMR: 0.99 (t, 3H, J = 7.3 Hz); 1.86 (m,2H); 4.10 (s, and PA) 3H); 4.77 (t, 1H, J = 6.4 Hz); 7.37-7.50 (m, 4H);7.65 (d, 1H, J = 7.6 Hz); 8.06 (d, 2H, J = 7.0 Hz). 4-15(2-methoxy-6-phenylpyridin-3- Yield: 31%. Appearance: yellow oil.yl)methyl-4- ¹H NMR: 2.51 (s, 3H); 4.13 (s, 3H); 4.67 (s, 2H);methylbenzenesulfonate 7.37-7.51 (m, 6H); 7.72 (d, 1H, J = 7.6 Hz); 7.95(d, 2H, (Protocol SL and PA) J = 8.5 Hz); 8.07 (m, 2H). 4-163-(bromomethyl)-2-methoxy-6- Yield: 91%. Appearance: white solid.phenylpyridine (Protocol SM) ¹H NMR: 4.14 (s, 3H); 4.57 (s, 2H); 7.36(d, 1H, J = 7.6 Hz); 7.42-7.53 (m, 3H); 7.68 (d, 1H, J = 7.6 Hz); 8.06(m, 2H).

Example 5 Synthesis of the Intermediates of the Pyridine3-Carboxaldehyde and Ketone Type According to the Invention

Synthesis of the intermediates in FIG. 5 a is summarized in Table 5-1.

TABLE 5-1 Ex. Intermediates (Protocols) Details 5-12-methoxy-6-phenyl-pyridine- Yield: 63%. Appearance: white solid.3-carboxaldehyde (Protocol ¹H NMR: 4.20 (s, 3H); 7.50 (m, 4H); 8.11 (m,2H); 8.19 (d, SN and PA) 1H, J = 7.9 Hz); 10.40 (s, 1H). 5-32-methoxy-6-(4- Yield: 94%. Appearance: white solid.(trifluoromethyl)phenyl)- ¹H NMR: 4.16 (s, 3H); 7.48 (d, 1H, J = 7.9Hz); 7.72 (d, 2H, pyridine-3-carboxaldehyde J = 8.2 Hz); 8.16-8.19 (m,3H); 10.38 (s, 1H). (Protocol SN and PA) 5-42-methoxy-5-phenyl-pyridine- Yield: 63%. Appearance: white solid.3-carboxaldehyde (Protocol ¹H NMR: 4.14 (s, 3H); 7.38-7.43 (m, 1H);7.46-7.51 (m, SN and PA) 2H); 7.55-7.59 (m, 2H); 8.34 (d, 1H, J = 2.6Hz); 8.63 (d, 1H, J = 2.6 Hz); 10.44 (s, 1H). 5-6 5-bromo-2-methoxy-6-Yield: 63%. Appearance: white solid. phenylpyridine-3- ¹H NMR: 4.10 (s,3H); 7.48-7.51 (m, 3H); 7.77-7.82 (m, carboxaldehyde (Protocol SN 2H);8.35 (s, 1H); 10.33 (s, 1H). and PA) 5-7 2-methoxy-6-furyl-pyridine-3-Yield: 86%. Appearance: yellow solid. carboxaldehyde (Protocol SN ¹HNMR: 4.07 (s, 3H); 6.73-6.75 (m, 1H); 7.34 (d, 1H, and PA) J = 3.2 Hz);7.48 (d, 1H, J = 7.9 Hz); 7.97 (m, 1H); 8.14 (d, 1H, J = 7.9 Hz); 10.21(s, 1H). 5-8 1-(2-methoxy-6- Yield: 92%. Appearance: white solid.phenylpyridin-3-yl)propan-1- ¹H NMR: 1.21 (t, 3H, J = 7.2 Hz); 3.09 (q,2H, J = 7.2 Hz); one (Protocol SN and PA) 4.17 (s, 3H); 7.45-7.52 (m,4H); 8.10 (d, 2H, J = 7.9 Hz); 8.22 (d, 1H, J = 7.9 Hz). 5-92-ethylthio-6-phenyl-pyridine- Yield: 86%. Appearance: yellow oil.3-carboxaldehyde (Protocol ¹H NMR: 1.49 (t, 3H, J = 7.3 Hz); 3.42 (q,2H, J = 7.3 Hz); SN and PA) 7.51-7.55 (m, 3H); 7.62 (d, 1H, J = 7.9 Hz);8.08 (d, 1H, J = 7.9 Hz); 8.12-8.15 (m, 2H); 10.27 (s, 1H). 5-102-methoxy-6-(parabiphenyl)- Yield: 79%. Appearance: white solid.pyridine-3-carboxaldehyde ¹H NMR: 4.22 (s, 3H); 7.41-7.43 (m, 1H);7.49-.756 (m, (Protocol SN and PA) 3H); 7.66-7.69 (m, 2H); 7.73-7.76 (m,2H); 8.20-8.22 (m, 3H); 10.41 (s, 1H). 5-11 2-methoxy-6-(3- Yield: 68%.Appearance: white solid (trifluoromethyl)phenyl)- ¹H NMR: 4.21 (s, 3H);7.53 (d, 1H, J = 7.9 Hz); 7.64 (t, 1H, pyridine-3-carboxaldehyde J = 7.9Hz); 7.73 (d, 1H, J = 7.9 Hz); 8.23 (d, 1H, J = 7.9 Hz); (Protocol SNand PA) 8.29 (d, 1H, J = 7.9 Hz); 8.37 (s, 1H); 10.41 (s, 1H). 5-122-methoxy-5-(4- Yield: 70%. Appearance: white solid(trifluoromethyl)phenyl)- ¹H NMR: 4.15 (s, 3H); 7.68 (d, 2H, J = 8.2Hz); 7.73 (d, 2H, pyridine-3-carboxaldehyde J = 8.2 Hz); 8.35 (d, 1H, J= 2.7 Hz); 8.65 (d, 1H, J = 2.7 Hz); (Protocol SN and PA) 10.44 (s, 1H).5-13 2-methoxy-5-(3- Yield: 58%. Appearance: white solid.(trifluoromethyl)phenyl)- ¹H NMR: 4.15 (s, 3H); 7.55-7.68 (m, 2H); 7.74(d, 1H, pyridine-3-carboxaldehyde J = 7.3 Hz); 7.81 (s, 1H); 8.34 (d,1H, J = 2.6 Hz); 8.64 (d, 1H, (Protocol SN and PA) J = 2.6 Hz); 10.45(s, 1H). 5-14 2,6-dimethoxy-5-phenyl- Yield: 93%. Appearance: whitesolid. pyridine-3-carboxaldehyde ¹H NMR: 4.07 (s, 3H); 4.12 (s, 3H);7.32-7.45 (m, 3H); (Protocol SN and PA) 7.50-7.54 (m, 2H); 8.13 (s, 1H);10.27 (s, 1H). 5-15 2-methoxy-5-(4- Yield: 58%. Appearance: white solid.chlorophenyl)-pyridine-3- ¹H NMR: 4.14 (s, 3H); 7.45 (d, 2H, J = 8.8Hz); 7.49 (d, 2H, carboxaldehyde (Protocol SN J = 8.8 Hz); 8.30 (d, 1H,J = 2.6 Hz); 8.59 (d, 1H, J = 2.6 Hz); and PA) 10.43 (s, 1H). 5-162-methoxy-5-(naphthalen-2- Yield: 75%. Appearance: white solid.yl)-pyridine-3- ¹H NMR: 4.16 (s, 3H); 7.50-7.57 (m, 2H); 7.70 (dd, 1H,carboxaldehyde (Protocol SN J = 1.9 Hz J = 8.5 Hz); 7.87-7.97 (m, 3H);8.03 (d, 1H, and PA) J = 1.5 Hz); 8.46 (d, 1H, J = 2.6 Hz); 8.76 (d, 1H,J = 2.6 Hz); 10.47 (s, 1H). 5-17 2-ethoxy-6-phenyl-pyridine-3- Yield:87%. Appearance: white solid. carboxaldehyde (Protocol SN ¹H NMR: 1.52(t, 3H, J = 7.0 Hz); 4.67 (q, 2H, J = 7.0 Hz); and PA) 7.44-7.54 (m,4H); 8.07-8.11 (m, 2H); 8.18 (d, 1H, J = 7.9 Hz); 10.42 (s, 1H). 5-182-isopropoxy-6-phenyl- Yield: 77%. Appearance: colorless oil.pyridine-3-carboxaldehyde ¹H NMR: 1.48 (s, 3H); 1.50 (s, 3H); 5.64-5.72(m, 1H); (Protocol SN and PA) 7.43-7.53 (m, 4H); 8.07-8.10 (m, 2H); 8.17(d, 1H, J = 7.9 Hz); 10.40 (s, 1H).

Synthesis of the intermediates in FIGS. 5 b and 5 c is summarized inTable 5-2.

TABLE 5-2 Ex. No. and type of Stage (Protocol) Details 5-22-tert-butoxy-6-phenyl-pyridine-3- Yield: 83%. Appearance: white solid.carboxaldehyde (Protocol SO and ¹H NMR: 1.76 (s, 9H); 7.42-7.53 (m, 4H);8.07 (m, PA) 2H); 8.16 (d, 1H, J = 8.2 Hz); 10.36 (s, 1H). 5-5 Stage 1:Preparation of 5,6- Yield: 59%. Appearance: yellow solid.diphenyl-2-oxo-pyridine-3- ¹H NMR: 7.07-7.10 (m, 2H); 7.25-7.43 (m, 8H);carboxaldehyde (Protocol SP and 8.23 (s, 1H); 10.27 (s, 1H). PA) Stage2: Obtaining 2-methoxy- Yield: 16%. Appearance: white solid.5,6-diphenyl-pyridine-3- ¹H NMR: 4.18 (s, 3H); 7.14-7.20 (m, 2H);carboxaldehyde (Protocol SF and 7.26-7.34 (m, 6H); 7.44-7.47 (m, 2H);8.16 (s, 1H); 10.44 (s, PA) 1H).

Example 6 Synthesis of the Intermediates of the Phenol, Thiophenol,Aniline Type

Synthesis of the intermediates in FIGS. 6 a, 6 c, and 6 e requires 2stages and is summarized in Table 6-1.

TABLE 6-1 Ex. No. and type of Stage (Protocol) Details 6-1 Stage 1:Preparation of ethyl 2-(4- Yield: 70%. Appearance: colorless oil.(benzyloxy)phenoxy)-2- ¹H NMR: 1.3 (t, 3H, J = 7.3 Hz); 1.56 (s, 6H);4.26 (q, methylpropanoate (Protocol SQ 2H, J = 7.3 Hz); 5.02 (s, 2H);6.87 (s, 4H); and PA) 7.32-7.36 (m, 5H). Stage 2: Obtaining ethyl 2-(4-Yield: 94%. Appearance: pink solid. hydroxyphenoxy)-2- ¹H NMR: 1.29 (t,3H, J = 7.0 Hz); 1.53 (s, 6H); 4.26 (q, methylpropanoate (Protocol SR)2H, J = 7.0 Hz); 6.70 (d, 2H, J = 9.0 Hz); 6.80 (d, 2H, J = 9.0 Hz). 6-2Stage 1: Preparation of tert-butyl Yield: quantitative. Appearance:colorless oil. 2-(4- ¹H NMR: 1.5 (s, 9H); 4.48 (s, 2H); 5.03 (s, 2H);(benzyloxy)phenoxy)ethanoate 6.84-6.94 (m, 4H); 7.33-7.46 (m, 5H).(Protocol SQ) Stage 2: Obtaining tert-butyl 2-(4- Yield: 97%.Appearance: white solid. hydroxyphenoxy)ethanoate ¹H NMR: 1.48 (s, 9H);4.47 (s, 2H); 6.75-6.83 (m, 4H). (Protocol SR and PD) 6-3 Stage 1:Preparation of ethyl 2-(4- Yield: 92%. Appearance: colorless oil.(benzyloxy)phenoxy)propanoate ¹H NMR: 1.28 (t, 3H, J = 7.2 Hz); 1.63 (d,3H, J = 6.9 Hz); (Protocol SQ and PA) 4.24 (q, 2H, J = 7.2 Hz); 4.68 (q,1H, J = 6.9 Hz); 5.03 (s, 2H); 6.85-6.94 (m, 4H); 7.32-7.46 (m, 5H).Stage 2: Obtaining ethyl 2-(4- Yield: 86%. Appearance: yellow oil.hydroxyphenoxy)propanoate ¹H NMR: 1.26 (t, 3H, J = 7.0 Hz); 1.59 (d, 3H,J = 6.7 Hz); (Protocol SR and PA) 4.23 (q, 2H, J = 7.3 Hz); 4.67 (q, 1H,J = 6.7 Hz); 6.71-6.78 (m, 4H). 6-4 Stage 1: Preparation of ethyl 2-(4-Yield: 80%. Appearance: white solid. (benzyloxy)phenoxy)ethanoate ¹HNMR: 1.32 (t, 3H, J = 7.0 Hz); 4.28 (q, 2H, J = 7.0 Hz); (Protocol SQand PA) 4.59 (s, 2H); 5.03 (s, 2H); 6.86-6.95 (m, 4H); 7.28-7.50 (m,5H). Stage 2: Obtaining ethyl 2-(4- Yield: 95%. Appearance: white solid.hydroxyphenoxy) ethanoate ¹H NMR: 1.31 (t, 3H, J = 7.2 Hz); 4.28 (q, 2H,J = 7.2 Hz); (Protocol SR) 4.57 (s, 2H); 5.03 (s, 1H); 6.74-6.83 (m,4H). 6-5 Stage 1: Preparation of tert-butyl Yield: 71%. Appearance:white solid. 2-(4-(benzyloxy)phenoxy)2- ¹H NMR: 1.47 (s, 9H); 1.53 (s,6H); 5.02 (s, 2H); methylpropanoate (Protocol SQ 6.87 (s, 4H); 7.33-7.46(m, 5H). and PA) Stage 2: Obtaining tert-butyl 2-(4- Yield: 64%.Appearance: white solid. hydroxyphenoxy)-2- ¹H NMR: 1.48 (s, 9H); 1.52(s, 6H); 3.80 (s, 1H); methylpropanoate (Protocol SR 6.69-6.73 (m, 2H);6.78-6.83 (m, 2H). and PA) 6-6 Stage 1: Preparation of tert-butyl Yield:60%. Appearance: ochre solid. 2-(4-nitrophenoxy)ethanoate ¹H NMR: 1.5(s, 9H); 4.63 (s, 2H); 6.96 (d, 2H, (Protocol SQ and PD) J = 9.3 Hz);8.22 (d, 2H, J = 9.3 Hz). Stage 2: Obtaining tert-butyl 2-(4- Yield:quantitative. Appearance: pink/red solid aminophenoxy)ethanoate ¹H NMR:1.49 (s, 9H); 3.35 (s (broad), 2H); 4.44 (s, (Protocol SR) 2H); 6.57 (d,2H, J = 8.8 Hz); 6.76 (d, 2H, J = 8.8 Hz). 6-7 Stage 1: Preparation ofethyl 2-(4- Yield: 80%. Appearance: white solid.(tertbutylcarbonylamino)phenoxy) ¹H NMR: 1.26 (t, 3H, J = 7.3 Hz); 1.52(s, 9H); 1.62 (d, propanoate (Protocol SQ and PD) 3H, J = 6.8 Hz); 4.21(q, 2H, J = 7.3 Hz); 4.70 (q, 1H, J = 6.8 Hz); 6.37 (s (broad), 1H);6.83 (d, 2H, J = 9.0 Hz); 7.26 (d, 2H, J = 9.0 Hz). Stage 2: Obtainingethyl 2-(4- Yield: 99%. Appearance: white solid. aminophenoxy)propanoate¹H NMR: 1.17 (t, 3H, J = 7.2 Hz); 1.15 (d, 3H, hydrochloride (ProtocolSS and J = 6.7 Hz); 4.13 (q, 2H, J = 7.2 Hz); 4.99 (q, 1H, PE) J = 6.7Hz); 6.99 (d, 2H, J = 8.8 Hz); 7.31 (d, 2H, J = 8.8 Hz); 10.28 (s(broad), 3H). 6-8 Stage 1: Preparation of ethyl 2-(4- Yield:quantitative. Appearance: white solid. (tertbutylcarbonylamino)phenoxy)¹H NMR: 1.29 (t, 3H, J = 7.0 Hz); 1.51 (s, 9H); 4.27 (q, ethanoate(Protocol SQ) 2H, J = 7.0 Hz); 4.59 (s, 2H); 6.44 (s (broad), 1H); 6.85(d, 2H, J = 8.8 Hz); 7.28 (d, 2H, J = 8.8 Hz). Stage 2: Obtaining ethyl2-(4- Yield: 86%. Appearance: pink solid aminophenoxy)ethanoate ¹H NMR:1.20 (t, 3H, J = 7.0 Hz); 4.16 (q, 2H, hydrochloride (Protocol SS and J= 7.0 Hz); 4.81 (s, 2H); 7.03 (d, 2H, J = 8.8 Hz); PE) 7.33 (d, 2H, J =8.8 Hz); 10.26 (s (broad), 3H). 6-9 Stage 1: Preparation of ethyl 2-(4-Yield: 95%. Appearance: colorless oil. (tertbutylcarbonylamino)phenoxy)-¹H NMR: 1.28 (t, 3H, J = 7.0 Hz); 1.52 (s, 9H); 1.56 (s,2-methyl-propanoate (Protocol 6H); 4.23 (q, 2H, J = 7.0 Hz); 6.39 (s(broad), 1H); SQ and PD) 6.83 (d, 2H, J = 9.0 Hz); 7.24 (d, 2H, J = 9.0Hz). Stage 2: Obtaining ethyl 2-(4- Yield: 89%. Appearance: white solid.aminophenoxy)-2- ¹H NMR: 1.17 (t, 3H, J = 7.0 Hz); 1.53 (s, 6H); 4.15(q, methylpropanoate hydrochloride 2H, J = 7.0 Hz); 6.88 (d, 2H, J = 8.8Hz); 7.29 (d, 2H, (Protocol SS and PE) J = 8.8 Hz); 10.24 (s (broad),3H). 6-11 Stage 1: Preparation of tert-butyl Yield: 65%. Appearance:yellow solid 2-(4-nitrophenoxy)-2- ¹H NMR: 1.43 (s, 9H); 1.65 (s, 6H);6.86 (d, 2H, methylpropanoate (Protocol SQ J = 7.3 Hz); 8.22 (d, 2H, J =7.3 Hz). and PA) Stage 2: Obtaining tert-butyl 2-(4- Yield: 91%.Appearance: brown solid. aminophenoxy)-2- ¹H NMR: 1.46 (s, 9H); 1.5 (s,6H); 4.33 (s (broad), methylpropanoate (Protocol SR 2H); 6.69 (d, 2H, J= 8.8 Hz); 6.78 (d, 2H, J = 8.8 Hz). and PD) 6-12 Stage 1: Preparationof tert-butyl Yield: 11%. Appearance: green solid. 2-(3-nitrophenoxy)-2-¹H NMR: 1.47 (s, 9H); 1.62 (s, 6H); 7.17-7.20 (m, 1H); methylpropanoate(Protocol SQ 7.40 (t, 1H, J = 8.2 Hz); 7.68 (t, 1H, J = 2.3 Hz); and PA)7.83-7.86 (m, 1H). Stage 2: Obtaining tert-butyl 2-(3- Yield: 37%.Appearance: green solid. aminophenoxy)-2- ¹H NMR: 1.46 (s, 9H); 1.5 (s,6H); 4.33 (s (broad), methylpropanoate (Protocol SR 2H); 6.69 (d, 2H, J= 8.8 Hz); 6.78 (d, 2H, J = 8.8 Hz). and PD) 6-13 Stage 1: Preparationof tert-butyl Yield: 96%. Appearance: red-orange solid.2-(3-nitrophenoxy)ethanoate ¹H NMR: 1.51 (s, 9H); 4.62 (s, 2H); 7.27(dd, 1H, (Protocol SQ and PC) J = 2.0 Hz, J = 8.2 Hz); 7.46 (t, 1H, J =8.2 Hz); 7.71 (t, 1H, J = 2.0 Hz); 7.88 (d, 1H, J = 8.2 Hz). Stage 2:Obtaining tert-butyl 2-(3- Yield: 72%. Appearance: pink/red oil.aminophenoxy)ethanoate ¹H NMR: 1.49 (s, 9H); 4.48 (s, 2H); 5.35 (s(broad), (Protocol SR and PA) 2H); 6.48 (m, 3H); 7.12 (d, 2H, J = 7.9Hz). 6-20 Stage 1: Preparation of ethyl 2-(4- Yield: 99%. Appearance:yellow solid. nitro-2,6- ¹H NMR: 1.34 (t, 3H, J = 7.0 Hz); 2.40 (s, 6H);4.31 (q, dimethylphenoxy)ethanoate 2H, J = 7.0 Hz); 4.47 (s, 2H); 7.93(s, 2H). (Protocol SQ and PD) Stage 2: Obtaining ethyl 2-(4- Yield:quantitative. Appearance: colorless oil. amino-2,6- ¹H NMR: 1.33 (t, 3H,J = 7.0 Hz); 2.22 (s, 6H); 4.30 (q, dimethylphenoxy)ethanoate 2H, J =7.0 Hz); 4.33 (s, 2H); 6.34 (s, 2H). (Protocol SR) 6-21 Stage 1:Preparation of ethyl 3-(4- Yield: 57%. Appearance: yellow oil.nitrophenyl)-3-phenylacrylate ¹H NMR: 1.17 (t, 3H, J = 7.3 Hz); 4.08 (q,2H, J = 7.3 Hz); (Protocol ST and PD) 6.49 (s, 1H); 7.33-7.43 (m, 2H);7.54 (t, 2H, J = 7.9 Hz); 7.64-7.69 (m, 1H); 7.95 (d, 2H, J = 8.8 Hz);8.27 (d, 2H, J = 8.8 Hz). Stage 2: Obtaining ethyl 3-(4- Yield: 53%.Appearance: colorless oil. aminophenyl)-3- ¹H NMR: 1.12 (t, 3H, J = 7.0Hz); 2.99 (d, 2H, J = 8.2 Hz); phenylpropanoate (Protocol SR) 7.03 (q,2H, J = 7.3 Hz); 4.45 (t, 1H, J = 7.9 Hz); 6.61 (d, 2H, J = 8.5 Hz);7.02 (d, 2H, J = 8.5 Hz); 7.14-7.30 (m, 5H). 6-22 Stage 1: Preparationof ethyl 3-(2- Yield: 20%. Appearance: yellow solid.methoxy-4-nitrophenyl)acrylate ¹H NMR: 1.36 (t, 3H, J = 7.2 Hz); 4.01(s, 3H); 4.30 (q, (Protocol ST and PA) 2H, J = 7.2 Hz); 6.64 (d, 1H, J =16.2 Hz); 7.63 (d, 1H, J = 8.5 Hz); 7.78 (d, 1H, J = 2.0 Hz); 7.85 (dd,1H, J = 2.0 Hz J = 8.5 Hz); 7.95 (d, 1H, J = 16.2 Hz). Stage 2:Obtaining ethyl 3-(4- Yield: 64%. Appearance: colorless oil. amino-2- ¹HNMR: 1.25 (t, 3H, J = 7.0 Hz); 2.54 (t, 2H, J = 7.3 Hz);methoxyphenyl)propanoate 2.83 (t, 2H, J = 7.3 Hz); 3.78 (s, 3H); 4.12(q, 2H, (Protocol SR) J = 7.0 Hz); 6.20-6.24 (m, 2H); 6.92 (d, 1H, J =8.8 Hz). 6-23 Stage 1: Preparation of ethyl 3-(3- Yield: 43%.Appearance: yellow solid. methoxy-4-nitrophenyl)acrylate ¹H NMR: 1.36(t, 3H, J = 7.3 Hz); 4.00 (s, 3H); 4.30 (q, (Protocol ST and PA) 2H, J =7.3 Hz); 6.52 (d, 1H, J = 16.1 Hz); 7.18-7.21 (m, 2H); 7.65 (d, 1H, J =16.1 Hz); 7.88 (d, 1H, J = 8.8 Hz). Stage 2: Obtaining ethyl 3-(4-Yield: 99%. Appearance: colorless oil. amino-3- ¹H NMR: 1.25 (t, 3H, J =7.0 Hz); 2.58 (m, 2H); 2.87 (m, methoxyphenyl)propanoate 2H); 3.84 (s,3H); 4.13 (q, 2H, J = 7.0 Hz); (Protocol SR) 6.66-6.64 (m, 3H). 6-24Stage 1: Preparation of ethyl 3-(4- Yield: 84%. Appearance: yellowsolid. nitrophenyl)but-2-enoate (Protocol ¹H NMR: 1.34 (s, 3H, J = 7.2Hz); 2.59 (d, 3H, SQ and PD) J = 1.5 Hz); 4.24 (q, 2H, J = 7.2 Hz); 6.19(d, 1H, J = 1.5 Hz); 7.62 (d, 2H, J = 8.9 Hz); 8.23 (d, 2H, J = 8.9 Hz).Stage 2: Obtaining ethyl 3-(4- Yield: 59%. Appearance: colorless oilaminophenyl)butanoate (Protocol ¹H NMR: 1.20 (t, 3H, J = 7.0 Hz); 1.26(d, 3H, J = 7.0 Hz); SR) 2.44-2.60 (m, 2H); 3.12-3.22 (m, 1H); 3.57 (m,2H); 4.08 (q, 2H, J = 7.0 Hz); 6.64 (d, 2H, J = 8.3 Hz); 7.02 (d, 2H, J= 8.3 Hz).

Synthesis of the intermediates in FIGS. 6 b and 6 d requires a singlestage and it is summarized in Table 6-2.

TABLE 6-2 Ex. Intermediates (Protocol) Details 6-10 Ethyl2-(4-aminophenylthio)- Yield: 87%. Appearance: colorless oil.2-methylpropanoate ¹H NMR: 1.13 (t, 3H, J = 7.1 Hz); 1.33 (s, 6H); 4.00(q, 2H, (Protocol SQ and PA) J = 7.1 Hz); 5.47 (s, 2H); 6.51 (d, 2H, J =8.5 Hz); 7.04 (d, 2H, J = 8.5 Hz). 6-14 Tert-butyl 2-(4- Yield: 28%.Appearance: yellow oil. aminophenylthio)acetate ¹H NMR: 1.40 (s, 9H);3.37 (s, 2H); 3.77 (s(broad), 2H); (Protocol SQ and PA) 6.59 (d, 2H, J =8.5 Hz); 7.28 (d, 2H, J = 8.5 Hz). 6-15 Ethyl 3-(4- Yield: 86%.Appearance: white solid. aminophenyl)propanoate ¹H NMR: 1.12 (t, 3H, J =7.3 Hz); 2.60 (t, 2H, J = 7.3 Hz); hydrochloride (Protocol SS 2.85 (t,2H, J = 7.3 Hz); 4.00 (q, 2H, J = 7.3 Hz); 7.27 (d, 2H, and PE) J = 8.2Hz); 7.33 (d, 2H, J = 8.2 Hz). 6-16 Tert-butyl 2-(4- Yield: 79%.Appearance: white solid. aminophenylthio)-2- ¹H NMR: 1.39 (s, 6H); 1.43(s, 9H); 3.81 (s(broad), 2H); methylpropanoate (Protocol 6.60 (d, 2H, J= 8.5 Hz); 7.28 (d, 2H, J = 8.5 Hz). SQ and PA) 6-17 Ethyl 2-((4amino)phenylthio)ethanoate Yield: 41%. Appearance: colorless oil.(Protocol SQ and ¹H NMR: 1.21 (t, 3H, J = 7.2 Hz); 3.45 (s, 2H); 3.75(s, 2H); PA) 4.13 (q, 2H, J = 7.2 Hz); 6.61 (d, 2H, J = 8.5 Hz); 7.29(d, 2H, J = 8.5 Hz) 6-18 Ethyl 2-(4-aminophenylthio)- Yield: 29%.Appearance: colorless oil 2,2-difluoroacetate (Protocol ¹H NMR: 1.29 (t,3H, J = 7.0 Hz); 4.26 (q, 2H, J = 7.0 Hz); SQ and PA) 6.66 (d, 2H, J =8.8 Hz); 7.37 (d, 2H, J = 8.5 Hz). 6-19 Ethyl 2-(4-aminophenylthio)-Yield: 37%. Appearance: yellow oil. 2-phenylethanoate (Protocol ¹H NMR:1.18 (t, 3H, J = 7.3 Hz); 3.75 (s (broad), 2H); SQ and PA) 4.06-4.18 (m,2H); 4.73 (s, 1H); 6.54 (d, 2H, J = 8.8 Hz); 7.21 (d, 2H, J = 8.5 Hz);7.27-7.34 (m, 3H); 7.41-7.44 (m, 2H).

For Example 6-25(5-(1-(4-hydroxyphenyl)but-2-ynyl)-2,2-dimethyl-1,3-dioxane-4,6-dione),synthesis of this compound requires 2 stages. In the first (preparationof 5-(4-hydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione), asolution of 4-hydroxybenzaldehyde in water (1 mol/L) is heated to 75° C.Meldrum's acid (1.05 eq.) is added in portions, then the reactionmixture is stirred at 75° C. for 2 hours. The reaction mixture is cooledand stirred for 2 hours at 0° C. The precipitate is drained, then washedwith ice water and heptane (Yield: 90%; Appearance: yellow solid; ¹HNMR: 1.80 (s, 6H); 6.94 (d, 2H, J=8.8 Hz); 8.19 (d, 2H, J=8.8 Hz); 8.39(s, 1H)). In the second (obtaining5-(1-(4-hydroxyphenyl)but-2-ynyl)-2,2-dimethyl-1,3-dioxane-4,6-dione), asolution of the preceding intermediate in tetrahydrofuran (0.5 mol/L) isadded under inert atmosphere, dropwise (0.25 hours), to a solution of1-propylmagnesium bromide in tetrahydrofuran (0.5 mol/L, 2 eq.). Afterstirring for 0.25 hours at room temperature, the reaction mixture isdiluted with aqueous solution of ammonium chloride (0.6 N, 3 eq.),extracted with cyclohexane, and acidified (pH=2) with sodium bisulfate.The evaporation residue is used without other forms of purification(Yield: 98%; Appearance: yellow solid; ¹H NMR: 1.64 (s, 3H); 1.82 (s,3H); 1.83 (s, 3H); 4.46 (d, 1H, J=2.6 Hz); 4.73 (d, 1H, J=2.6 Hz); 6.76(d, 2H, J=8.5 Hz); 7.39 (d, 2H, J=8.5 Hz); 8.24 (s, 1H)).

Example 7 Synthesis of the Compounds According to the Invention

Synthesis of the compounds according to the invention in FIG. 7 arequires 2 or 3 stages and is summarized in Table 7-1.

TABLE 7-1 Cpd No. and type of Stage (Ex.; Protocol) Details 4 1:Preparation of tert-butyl 2-(4-((2- Yield: quantitative. Appearance:yellow oil methoxy-6-phenylpyridin-3- ¹H NMR: 1.49 (s, 9H); 4.11 (s,3H); 4.30 (s, 2H); yl)methylamino)-phenoxy)ethanoate 4.43 (s, 2H); 6.61(d, 2H, J = 8.8 Hz); 6.78 (d, 2H, (Ex. 5-1 and Ex. 6-6 with Protocol SXJ = 8.8 Hz); 7.31 (d, 1H, J = 7.6 Hz); 7.34-7.49 (m, and PA) 3H); 7.61(d, 1H, J = 7.6 Hz); 8.02 (m, 2H). 2: Obtaining 2-(4-(((2-methoxy-6-Yield: 81%. Appearance: white solid phenylpyridin- ¹H NMR: 4.03 (s, 3H);4.18 (s, 2H); 4.47 (s, 2H); 3yl)methyl)amino)phenoxy)ethanoic 6.50 (d,2H, J = 8.8 Hz); 6.68 (d, 2H, J = 8.8 Hz); acid 7.55-7.35 (m, 4H); 7.64(d, 1H, J = 7.6 Hz); (Protocol SW and PE) 8.06 (m, 2H). 8 1: Preparationof ethyl 2-(4-((2-tert- Yield: 51%. Appearance: white solidbutoxy-6-phenylpyridin-3- ¹H NMR: 1.29 (t, 3H, J = 7.0 Hz); 1.71 (s,9H); yl)methylamino)-phenoxy)ethanoate 4.23-4.29 (m, 4H); 4.53 (s, 2H);6.64 (d, 2H, J = 9.1 Hz); (Ex. 5-2 and Ex. 6-8 with Protocol SX 6.80 (d,2H, J = 9.1 Hz); 7.27 (d, 1H, J = 7.6 Hz); and PA) 7.35-7.47 (m, 3H);7.57 (d, 1H, J = 7.6 Hz); 8.0 (d, 2H, J = 7.3 Hz). 2: Obtaining2-(4-((2-tert-butyloxy-6- Yield: 63%. Appearance: white solid.phenylpyridin-3- ¹H NMR: 1.67 (s, 9H); 4.12 (s, 2H); 4.43 (s, 2H);yl)methyl)amino)phenoxy)ethanoic 6.48 (d, 2H, J = 9.1 Hz); 6.67 (d, 2H,J = 9.1 Hz); acid (Protocol SU and PA) 7.35-7.49 (m, 4H); 7.60 (d, 1H, J= 7.9 Hz); 7.99 (d, 2H, J = 7.3 Hz). 9 1: Preparation of ethyl2-(4-((2-tert- Yield: 79%. Appearance: orange-colored oil.butoxy-6-phenylpyridin-3- ¹H NMR: 1.28 (t, 3H, J = 7.3 Hz); 1.52 (s,6H); 1.71 (s, yl)methylamino)-phenoxy)-2-methyl- 9H); 4.19-4.26 (m, 4H);6.55 (d, 2H, J = 9.0 Hz); propanoate (Ex. 5-2 and Ex. 6-9 with 6.77 (d,2H, J = 9.0 Hz); 7.27 (d, 1H, J = 7.6 Hz); Protocol SX and PA) 7.35-7.48(m, 3H); 7.56 (d, 1H, J = 7.6 Hz); 7.99 (d, 2H, J = 7.7 Hz). 2:Obtaining 2-(4-(((2-tert-butyloxy-6- Yield: 46%. Appearance: yellowsolid. phenylpyridin-3- ¹H NMR: 1.36 (s, 6H); 1.66 (s, 9H); 4.11 (s,2H); yl)methyl)amino)phenoxy)-2-methyl- 6.46 (d, 2H, J = 8.8 Hz); 6.67(d, 2H, J = 8.8 Hz); propanoic acid (Protocol SU and PD) 7.35-7.49 (m,4H); 7.61 (d, 1H, J = 7.6 Hz); 8.0 (d, 2H, J = 7.0 Hz). 10 1:Preparation of ethyl 2-(4-((2-tert- Yield: 52%. Appearance: yellow oil.butoxy-6-phenylpyridin-3- ¹H NMR: 1.24 (t, 3H, J = 7.3 Hz); 1.57 (d, 3H,yl)methylamino)-phenoxy)propanoate J = 6.7 Hz); 1.71 (s, 9H); 4.17-4.23(m, 4H); 4.61 (q, (Ex. 5-2 and Ex. 6-7 with Protocol SX 1H, J = 6.7 Hz);6.60 (d, 2H, J = 9.0 Hz); 6.77 (d, 2H, and PA) J = 9.0 Hz); 7.26 (d, 1H,J = 7.6 Hz); 7.37-7.47 (m, 3H); 7.56 (d, 1H, J = 7.6 Hz); 7.99 (d, 2H, J= 7.0 Hz). 2: Obtaining 2-(4-(((2-tert-butyloxy-6- Yield: 18%.Appearance: white solid. phenylpyridin-3- ¹H NMR: 1.4 (d, 3H, J = 6.7Hz); 1.66 (s, 9 Hz); yl)methyl)amino)phenoxy)propanoic 4.11 (s, 2H);4.50-4.57 (m, 1H); 6.48 (d, 2H, J = 8.8 Hz); acid (Protocol SU and PA)6.64 (d, 2H, J = 8.8 Hz); 7.35-7.40 (m, 1H); 7.44-7.49 (m, 3H); 7.6 (d,1H, J = 7.6 Hz); 7.99 (d, 2H, J = 7.3 Hz). 11 1: Preparation of ethyl2-(4-((2- Yield: 87%. Appearance: orange-colored oilmethoxy-6-phenylpyridin-3- ¹H NMR: 1.22 (t, 3H, J = 7.3 Hz); 1.45 (s,6H); yl)methylamino)phenylthio)-2-methyl- 4.04-4.16 (m, 5H); 4.35 (s,2H); 6.56 (d, 2H, J = 8.5 Hz); propanoate (Ex. 5-1 and Ex. 6-10 7.26 (d,2H, J = 8.5 Hz); 7.31 (d, 1H, J = 7.6 Hz); with Protocol SX and PA)7.37-7.51 (m, 3H); 7.59 (d, 1H, J = 7.6 Hz); 8.19 (d, 2H, J = 8.5 Hz).2: Obtaining 2-(4-(((2-methoxy-6- Yield: 57%. Appearance: beige solidphenylpyridin-3-yl)methyl)amino)phenylthio)- ¹H NMR: 1.29 (s, 6H); 4.04(s, 3H); 4.24 (d, 2H, 2-methyl- J = 5.8 Hz); 6.54 (m, 3H); 7.14 (d, 2H,J = 8.5 Hz); propanoic acid (Protocol SU and PA) 7.37-7.54 (m, 4H); 7.64(d, 1H, J = 7.6 Hz); 8.08 (d, 2H, J = 7.0 Hz), 12.34 (s, 1H). 12 1:Preparation of tert-butyl 2-(4-((2- Yield: 71%. Appearance: yellow oil.methoxy-6-phenylpyridin-3- ¹H NMR: 1.44 (s, 9H); 1.49 (s, 6H); 4.09 (s,3H); yl)methylamino)phenoxy)-2-methyl- 4.32 (s, 2H); 6.61-6.72 (m, 2H);6.79 (d, 2H, propanoate (Ex. 5-1 and Ex. 6-11 J = 9.1 Hz); 7.30 (d, 1H,J = 7.6 Hz); 7.36-7.48 (m, 3H); with Protocol SX and PA) 7.62-7.65 (m,1H); 8.03 (d, 2H, J = 8.2 Hz). 2: Obtaining 2-(4-(((2-methoxy-6- Yield:70%. Appearance: white solid phenylpyridin-3- ¹H NMR: 1.36 (s, 6H); 4.03(s, 3H); 4.17 (s, 2H); yl)methyl)amino)phenoxy)-2-methyl- 5.89(s(broad), 1H); 6.47 (d, 2H, J = 9.1 Hz); 6.67 (d, propanoic acid(Protocol SW and PC) 2H, J = 9.1 Hz); 7.37-7.54 (m, 4H); 7.66 (d, 1H, J= 7.6 Hz); 8.07 (d, 2H, J = 7.0 Hz). 16 1: Preparation of tert-butyl2-(4-((2- Yield: 99%. Appearance: yellow oil. methoxy-6-phenylpyridin-3-¹H NMR: 1.40 (s, 9H); 3.38 (s, 2H); 4.12 (s, 3H); yl)methylamino)- 4.34(s, 2H); 6.58 (d, 2H, J = 8.8 Hz); 7.29-7.31 (m, phenylthio)ethanoate(Ex. 5-1 and 3H); 7.37-7.48 (m, 3H); 7.58 (d, 1H, J = 7.6 Hz); Ex. 6-14with Protocol SX and PA) 8.04 (d, 2H, J = 8.5 Hz). 2: Obtaining2-(4-(((2-methoxy-6- Yield: 64%. Appearance: white solidphenylpyridin-3- ¹H NMR: 3.49 (s, 2H); 4.11 (s, 3H); 4.34 (s, 2H);yl)methyl)amino)phenylthio)ethanoic 6.58 (d, 2H, J = 8.0 Hz); 7.30-7.48(m, 6H); 7.58 (d, acid (Protocol SW and PC) 1H, J = 7.1 Hz); 8.03 (d,2H, J = 8.0 Hz). 19 1: Preparation of ethyl 3-(4-((2- Yield: 53%.Appearance: yellow oil. methoxy-6-phenylpyridin-3- ¹H NMR: 1.24 (t, 3H,J = 7.3 Hz); 2.56 (t, 2H, yl)methylamino)phenyl)propanoate J = 8.2 Hz);2.84 (t, 2H, J = 8.2 Hz); 4.09-4.16 (m, 5H); (Ex. 5-1 and Ex. 6-15 withProtocol 4.33 (s, 2H); 6.64 (d, 2H, J = 8.2 Hz); 7.03 (d, 2H, SX and PA)J = 8.2 Hz); 7.30 (d, 1H, J = 7.6 Hz); 7.36-7.48 (m, 3H); 7.63 (d, 1H, J= 7.6 Hz); 8.04 (d, 2H, J = 7.3 Hz). 2: Obtaining 3-(4-(((2-methoxy-6-Yield: 73%. Appearance: yellow solid. phenylpyridin-3- ¹H NMR: 2.62 (t,2H, J = 7.6 Hz); 2.85 (t, 2H, yl)methyl)amino)phenyl) propanoic J = 7.6Hz); 4.10 (s, 3H); 4.34 (s, 2H); 6.66 (d, 2H, acid (Protocol SU and PC)J = 8.2 Hz); 7.03 (d, 2H, J = 8.2 Hz); 7.30 (d, 1H, J = 7.6 Hz);7.36-7.48 (m, 3H); 7.63 (d, 1H, J = 7.6 Hz); 8.04 (m, 2H). 22 1:Preparation of tert-butyl 2-(4-((2- Yield: 92%; Appearance: yellow oil;methoxy-6-(4- ¹H NMR: 1.39 (s, 6H); 1.43 (s, 9H); 4.12 (s, 3H);(trifluoromethyl)phenyl)pyridin-3- 4.37 (s, 2H); 6.56 (d, 2H, J = 8.5Hz); 7.30 (d, 2H, yl)methylamino)phenylthio)-2- J = 8.5 Hz); 7.34 (d,1H, J = 7.6 Hz); 7.62 (d, 1H, methylpropanoate (Ex. 5-3 and Ex. 6- J =7.6 Hz); 7.71 (d, 2H, J = 8.2 Hz); 8.50 (d, 2H, 16 with Protocol SX andPA) J = 8.2 Hz). 2: Obtaining 2-(4-(((2-methoxy-6-(4- Yield: 55%;Appearance: yellow solid. (trifluoromethyl)phenyl)pyridin-3- ¹H NMR:1.47 (s, 6H); 4.11 (s, 3H); 4.36 (s, 2H); yl)methyl)amino)phenylthio)-2-6.57 (d, 2H, J = 8.8 Hz); 7.3-7.35 (m, 3H); 7.61 (d, methylpropanoicacid (Protocol SW 1H, J = 7.6 Hz); 7.69 (d, 2H, J = 8.0 Hz); 8.12 (d,2H, and PB) J = 8.0 Hz 23 1: Preparation of tert-butyl 2-(4-((2- Yield:96%. Appearance: yellow-orange oil. methoxy-6-(4- ¹H NMR: 1.41 (s, 9H);3.37 (s, 2H); 4.12 (s, 3H); (trifluoromethyl)phenyl)pyridin-3- 4.42 (s,2H); 6.57 (d, 2H, J = 8.6 Hz); 7.30-7.35 (m,yl)methylamino)phenylthio)ethanoate 3H); 7.62 (d, 1H, J = 7.6 Hz); 7.71(d, 2H, J = 8.5 Hz); (Ex. 5-3 and Ex. 6-14 with Protocol 8.14 (d, 2H, J= 7.9 Hz). SX and PA) 2: Obtaining 2-(4-(((2-methoxy-6-(4- Yield: 21%.Appearance: yellow solid. (trifluoromethyl)phenyl)pyridin-3- ¹H NMR:3.50 (s, 2H); 4.12 (s, 3H); 4.36 (s, 2H);yl)methyl)amino)phenylthio)ethanoic 6.58 (d, 2H, J = 8.8 Hz); 7.32-7.36(m, 3H); 7.61 (d, acid (Protocol SW and PB) 1H, J = 7.6 Hz); 7.70 (d,2H, J = 8.2 Hz); 8.14 (d, 2H, J = 8.2 Hz). 26 1: Preparation of ethyl2-(4-((2- Yield: 73%. Appearance: yellow oil methoxy-5-phenylpyridin-3-¹H NMR: 1.19 (t, 3H, J = 7.3 Hz); 3.48 (s, 2H); 4.03 (s,yl)methylamino)- 3H); 4.12 (q, 2H, J = 7.3 Hz); 4.37 (s, 2H); 6.77 (d,phenylthio)ethanoate (Ex. 5-4 and 2H, J = 7.9 Hz); 7.29-7.50 (m, 8H);7.84 (d, 1H, Ex. 6-17 with Protocol SX and PA) J = 2.0 Hz); 8.30 (d, 1H,J = 2.0 Hz). 2: Obtaining 2-(4-(((2-methoxy-5- Yield: 66%. Appearance:white solid. phenylpyridin-3- ¹H NMR: 3.44 (s, 2H); 3.97 (s, 3H); 4.24(d, 2H, yl)methyl)amino)phenylthio) ethanoic J = 5.0 Hz); 6.39 (s(broad), 1H); 6.56 (d, 2H, acid (Protocol SU and PE) J = 8.6 Hz); 7.17(d, 2H, J = 8.6 Hz); 7.31-7.37 (m, 1H); 7.41-7.46 (m, 2H); 7.54 (d, 2H,J = 7.3 Hz); 7.86 (d, 1H, J = 2.3 Hz); 8.36 (d, 1H, J = 2.3 Hz); 12.44(s, 1H). 27 1: Preparation of ethyl 2-(4-((2- Yield: 88%. Appearance:yellow oil. methoxy-6-phenylpyridin-3- ¹H NMR: 1.26 (t, 3H, J = 7.3 Hz);4.11 (s, 3H); 4.24 (q, yl)methylamino)phenylthio)-2-2- 2H, J = 7.3 Hz);4.37 (s, 2H); 6.65 (d, 2H, J = 8.8 Hz); difluoroethanoate (Ex. 5-1 andEx. 6- 7.32 (d, 1H, J = 7.6 Hz); 7.38-7.49 (m, 5H); 7.58 (d, 1H, 18 withProtocol SX and PA) J = 7.3 Hz); 8.04 (d, 2H, J = 7.0 Hz). 2: Obtaining2-(4-(((2-methoxy-6- Yield: 36%. Appearance: white solid.phenylpyridin-3-yl)- ¹H NMR: 4.04 (s, 3H); 4.27 (s, 2H); 6.62 (d, 2H,methyl)amino)phenylthio)-2,2-difluoro- J = 8.5 Hz); 7.26 (d, 2H, J = 8.5Hz); 7.37-7.54 (m, 4H); ethanoic acid (Protocol SU and PC) 7.62 (d, 1H,J = 7.6 Hz); 8.07 (d, 2H, J = 7.3 Hz). 28 1: Preparation of ethyl2-(4-((2- Yield: 73%. Appearance: colorless oil.methoxy-5-6-diphenylpyridin-3- ¹H NMR: 1.19 (t, 3H, J = 7.0 Hz); 3.46(s, 2H); 4.08 (s, yl)methylamino)-phenylthio)ethanoate 3H); 4.12 (q, 2H,J = 7.0 Hz); 4.38 (s, 2H); 6.66 (d, 2H, (Ex. 5-5 and Ex. 6-17 with J =8.5 Hz); 7.09-7.12 (m, 2H); 7.18-7.25 (m, 6H); Protocol SX and PA) 7.34(d, 2H, J = 8.8 Hz); 7.37-7.40 (m, 2H); 7.59 (s, 1H). 2: Obtaining2-(4-(((2-methoxy-5,6- Yield: 6.56%. Appearance: white solid.diphenylpyridin-3- ¹H NMR: 3.38 (s, 2H); 4.00 (s, 3H); 4.26 (d, 2H,yl)methyl)amino)phenylthio)ethanoic J = 5.6 Hz); 6.31 (m, 1H); 6.55 (d,2H, J = 8.5 Hz); acid (Protocol SU and PA) 7.05 (dd, 2H, J = 2.3 Hz J =7.9 Hz); 7.13 (d, 2H, J = 8.5 Hz); 3: Protocol PC 7.23-7.32 (m, 8H);7.59 (s, 1H). 29 1: Preparation of ethyl 2-(4-((2- Yield: 58%.Appearance: colorless oil. methoxy-5-6-diphenylpyridin-3-yl)methyl ¹HNMR: 1.23 (t, 3H, J = 7.1 Hz); 3.50 (s, 2H); 4.00 (s,amino)-phenylthio)ethanoate 3H); 4.15 (q, 2H, J = 7.1 Hz); 4.34 (s, 2H);6.72 (m, (Ex. 5-6 and Ex. 6-17 with Protocol 2H); 7.31-7.46 (m, 5H);7.74-7.87 (m, 3H). SX and PA) 2: Obtaining 2-(4-(((2-methoxy-5- Yield:34%. Appearance: white solid. bromo-6-phenylpyridin-3- ¹H NMR: 3.46 (s,2H); 3.93 (s, 3H); 4.22 (d, 2H, yl)methyl)amino) phenylthio)- J = 5.8Hz); 6.45 (t, 1H, J = 5.8 Hz); 6.56 (d, 2H, ethanoic acid (Protocol SUand PA) J = 8.6 Hz); 7.19 (d, 2H, J = 8.6 Hz); 7.42-7.50 (m, 3H); 3:Protocol PC 7.67 (m, 2H); 7.80 (s, 1H); 12.51 (s, 1H). 30 1: Preparationof ethyl 2-(4-((2- Yield: 85%. Appearance: yellow oil.methoxy-6-furylpyridin-3- ¹H NMR: 1.21 (t, 3H, J = 7.0 Hz); 3.49 (s,2H); 4.02 (s, yl)methylamino)- 3H); 4.15 (q, 2H, J = 7.0 Hz); 4.32 (s,2H); phenylthio)ethanoate (Ex. 5-e and 6.50-6.53 (m, 1H); 6.76 (d, 2H, J= 8.6 Hz); 7.00 (d, 1H, Ex. 6-17 with Protocol SX and PA) J = 2.9 Hz);7.20 (d, 1H, J = 7.6 Hz); 7.31 (d, 2H, J = 8.6 Hz); 7.49-7.54 (m, 1H);7.60 (d, 1H, J = 7.6 Hz). 2: Obtaining 2-(4-(((2-methoxy-6- Yield: 57%.Appearance: beige solid. furylpyridin-3- ¹H NMR: 3.44 (s, 2H); 3.98 (s,3H); 4.19 (d, 2H, yl)methyl)amino)phenylthio)ethanoic J = 5.6 Hz); 6.39(t, 1H, J = 5.6 Hz); 6.51 (d, 2H, acid (Protocol SU and PC) J = 8.8 Hz);6.61-6.63 (m, 1H); 7.02 (d, 1H, J = 3.2 Hz); 7.16 (d, 2H, J = 8.8 Hz);7.28 (d, 1H, J = 7.6 Hz); 7.59 (d, 1H, J = 7.6 Hz); 7.78 (m, 1H). 31 1:Preparation of ethyl 3-(4-((2- Yield: 68%. Appearance: yellow oil.methoxy-6-furylpyridin-3- ¹H NMR: 1.13 (t, 3H, J = 7.1 Hz); 2.46 (t, 2H,J = 7.3 Hz); yl)methylamino)-phenyl)propanoate 2.66 (t, 2H, J = 7.3 Hz);3.99 (s, 3H); 4.00 (q, 2H, (Ex. 5-6 and Ex. 6-15 with Protocol J = 7.1Hz); 4.17 (d, 2H, J = 6.0 Hz); 6.03 (t, 1H, SX and PA) J = 6.0 Hz); 6.46(d, 2H, J = 8.3 Hz); 6.61-6.63 (m, 1H); 6.90 (d, 2H, J = 8.3 Hz); 7.02(d, 1H, J = 3.2 Hz); 7.26 (d, 1H, J = 7.6 Hz); 7.59 (d, 1H, J = 7.6 Hz);7.79 (s, 1H). 2: Obtaining 3-(4-(((2-methoxy-6- Yield: 24%. Appearance:beige solid. furylpyridin-3- ¹H NMR: 2.41 (t, 2H, J = 7.6 Hz); 2.64 (t,2H, J = 7.6 Hz); yl)methyl)amino)phenyl)propanoic 3.99 (s, 3H); 4.17 (s,2H); 6.03 (s (broad), 1H); acid (Protocol SU and PC) 6.47 (d, 2H, J =8.2 Hz); 6.63 (m, 1H); 6.91 (d, 2H, J = 8.2 Hz); 7.03 (d, 1H, J = 3.2Hz); 7.26 (d, 1H, J = 7.6 Hz); 7.60 (d, 1H, J = 7.6 Hz); 7.79 (s, 1H).32 1: Preparation of ethyl 2-(4-((2- Yield: 75%. Appearance: yellow oil.methoxy-6-phenylpyridin-3- ¹H NMR: 1.16 (t, 3H, J = 7.0 Hz); 4.05-4.20(m, 5H); yl)methylamino)-phenylthio)-2- 4.33 (s, 2H); 4.69 (s, 1H); 6.53(d, 2H, J = 8.6 Hz); phenylethanoate (Ex. 5-1 and Ex. 6- 7.22 (d, 2H, J= 8.6 Hz); 7.28-7.33 (m, 4H); 7.39-7.49 (m, 19 with Protocol SX and PA)5H); 7.56 (d, 1H, J = 7.6 Hz); 8.02-8.05 (m, 2H). 2: Obtaining2-(4-(((2-methoxy-6- Yield: 58%. Appearance: white solid.phenylpyridin-3-yl)methyl)amino)phenylthio)- ¹H NMR: 4.03 (s, 3H); 4.21(d, 2H, J = 5.6 Hz); 4.71 (s, 2-phenyl- 1H); 6.43-6.48 (m, 3H); 7.07 (d,2H, J = 8.8 Hz); ethanoic acid (Protocol SU and PA) 7.25-7.59 (m, 10H);8.07 (d, 2H, J = 7.0 Hz). 3: Protocol PC 35 1: Preparation of ethyl2-(4-((2- Yield: 96%. Appearance: yellow oil. methoxy-6-phenylpyridin-3-¹H NMR (300 MHz, CDCl3, d in ppm): 1.33 (t, 3H,yl)methylamino)-2,6-dimethyl- J = 7.0 Hz); 2.23 (s, 6H); 4.11 (s, 3H);4.26-4.34 (m, phenoxy)ethanoate (Ex. 5-1 and Ex. 6H); 6.31 (s, 2H); 7.32(d, 1H, J = 7.6 Hz); 6-20 with Protocol SX and PA) 7.38-7.48 (m, 3H);7.61 (d, 1H, J = 7.6 Hz); 8.03-8.07 (d, 2H, J = 7.0 Hz). 2: Obtaining2-(4-(((2-methoxy-6- Yield: 6%. Appearance: white solid.phenylpyridin-3-yl)methyl)amino)-2,6- ¹H NMR: 2.08 (s, 6H); 4.03 (s,3H); 4.15 (m, 4H); dimethyl-phenoxy) ethanoic acid 6.21 (s, 2H);7.36-7.54 (m, 4H); 7.63 (d, 1H, (Protocol SU and PA) J = 7.6 Hz);8.06-8.09 (m, 2H). 36 1: Preparation of ethyl 3-(4-((2- Yield: 43%.Appearance: orange-colored oil. methoxy-6-(4- ¹H NMR: 1.24 (t, 3H, J =7.1 Hz); 2.56 (t, 2H, J = 7.5 Hz); (trifluoromethyl)phenyl)pyridin-3-2.85 (t, 2H, J = 7.5 Hz); 4.09 (s, 3H); 4.12 (q, 2H,yl)methylamino)phenyl)propanoate J = 7.1 Hz); 4.37 (s, 2H); 6.73-6.94(m, 2H); 7.05 (d, (Ex. 5-3 and Ex. 6-15 with Protocol 2H, J = 8.1 Hz);7.32 (d, 1H, J = 7.5 Hz); 7.66-7.72 (m, SX and PA) 3H); 8.13 (d, 2H, J =8.0 Hz). 2: Obtaining 3-(4-(((2-methoxy-6-(4- Yield: 58%. Appearance:white solid. trifluoromethyl)phenyl)pyridin-3- ¹H NMR: 2.39 (t, 2H, J =7.3 Hz); 2.63 (t, 2H, J = 7.3 Hz); yl)methyl)amino)-phenyl)-propanoic4.06 (s, 3H); 4.22 (d, 2H, J = 5.9 Hz); 6.05 (t, 1H, acid (Protocol SUand PA) J = 5.9 Hz); 6.48 (d, 2H, J = 8.3 Hz); 6.91 (d, 2H, J = 8.3 Hz);7.62-7.69 (m, 2H); 7.83 (d, 2H, J = 8.4 Hz); 8.29 (d, 2H, J = 8.4 Hz).38 1: Preparation of ethyl 3-(4-((2- Yield: 84%. Appearance: yellowsolid. (ethylthio)-6-phenylpyridin-3- ¹H NMR: 1.24 (t, 3H, J = 7.3 Hz);1.50 (t, 3H, J = 7.3 Hz); yl)methylamino)-phenyl)propanoate 2.56 (t, 2H,J = 7.6 Hz); 2.85 (t, 2H, J = 7.6 Hz); 3.41 (q, (Ex. 5-9 and Ex. 6-15with Protocol 2H, J = 7.3 Hz); 4.13 (q, 2H, J = 7.3 Hz); 4.32 (s, 2H);SX and PA) 6.57 (d, 2H, J = 8.5 Hz); 7.02 (d, 2H, J = 8.5 Hz); 7.40-7.50(m, 4H); 7.60 (d, 1H, J = 7.9 Hz); 8.04-8.07 (m, 2H). 2: Obtaining3-(4-(((2-(ethylthio)-6- Yield: 40%. Appearance: beige solid.phenylpyridin-3- ¹H NMR: 1.40 (t, 3H, J = 7.3 Hz); 2.41 (t, 2H, J = 7.3Hz); yl)methyl)amino)phenyl)-propanoic 2.64 (t, 2H, J = 7.3 Hz);3.30-3.38 (m, 2H); 4.16 (d, 2H, acid (Protocol SU and PA) J = 5.9 Hz);6.15 (t, 1H, J = 5.9 Hz); 6.44 (d, 2H, J = 8.5 Hz); 6.92 (d, 2H, J = 8.5Hz); 7.39-7.51 (m, 3H); 7.59-7.68 (m, 2H); 8.09 (d, 2H, J = 7.0 Hz);12.00 (s, 1H). 39 1: Preparation of ethyl 3-(4-((2- Yield: 84%.Appearance: yellow oil. methoxy-6-(parabiphenyl)pyridin-3- ¹H NMR: 1.25(t, 3H, J = 7.0 Hz); 2.57 (t, 2H, J = 7.3 Hz);yl)methyl-amino)phenyl)-propanoate 2.86 (t, 2H, J = 7.3 Hz); 4.10-4.17(m, 5H); 4.34 (s, 2H); (Ex. 5-10 and Ex. 6-15 with Protocol 6.61 (d, 2H,J = 8.5 Hz); 7.03 (d, 2H, J = 8.5 Hz); SX and PA) 7.34-7.41 (m, 2H);7.48 (m, 2H); 7.62-7.72 (m, 5H); 8.13 (d, 2H, J = 8.5 Hz). 2: Obtaining3-(4-(((2-methoxy-6- Yield: 60%. Appearance: beige solid.(parabiphenyl)pyridin-3- ¹H NMR: 2.41 (t, 2H, J = 7.3 Hz); 2.64 (t, 2H,J = 7.3 Hz); yl)methyl)amino)phenyl)-propanoic 4.06 (s, 3H); 4.21 (d,2H, J = 5.6 Hz); 6.03 (t, 1H, acid (Protocol SU and PA) J = 5.6 Hz);6.49 (d, 2H, J = 8.5 Hz); 6.91 (d, 2H, J = 8.5 Hz); 7.36-7.41 (m, 1H);7.49 (t, 2H, J = 7.0 Hz); 7.58 (d, 1H, J = 7.6 Hz); 7.64 (d, 1H, J = 7.6Hz); 7.72-7.79 (m, 4H); 8.17 (d, 2H, J = 8.5 Hz). 40 1: Preparation ofethyl 3-(4-((2- Yield: 86%. Appearance: yellow oil. methoxy-6-(3- ¹HNMR: 1.24 (t, 3H, J = 7.3 Hz); 2.56 (t, 2H, J = 7.3 Hz);(trifluoromethyl)phenyl)pyridin-3- 2.85 (t, 2H, J = 7.3 Hz); 4.09-4.17(m, 5H); 4.35 (s, 2H); yl)methylamino)phenyl)propanoate 6.59 (d, 2H, J =8.5 Hz); 7.02 (d, 2H, J = 8.5 Hz); 7.33 (d, (Ex. 5-11 and Ex. 6-15 withProtocol 1H, J = 7.6 Hz); 7.54-7.66 (m, 3H); 8.20 (d, 1H, SX and PA) J =7.6 Hz); 8.30 (s, 1H). 2: Obtaining 3-(4-(((2-methoxy-6-(3- Yield: 53%.Appearance: beige solid. (trifluoromethyl)phenyl)pyridin-3- ¹H NMR: 2.63(t, 2H, J = 7.6 Hz); 2.86 (t, 2H, J = 7.6 Hz);yl)methyl)amino)-phenyl)propanoic 4.12 (s, 3H); 4.34 (s, 2H); 6.59 (d,2H, J = 8.5 Hz); acid (Protocol SU and PA) 7.03 (d, 2H, J = 8.5 Hz);7.34 (d, 1H, J = 7.6 Hz); 7.54-7.66 (m, 3H); 8.20 (d, 1H, J = 7.6 Hz);8.30 (s, 1 H). 41 1: Preparation of ethyl 3-(4-((2- Yield: 72%.Appearance: colorless oil. methoxy-5-phenylpyridin-3- ¹H NMR (300 MHz,CDCl₃, d in ppm): 1.22 (t, 3H, yl)methylamino)-phenyl)propanoate J = 7.3Hz); 2.56 (t, 2H, J = 7.3 Hz); 2.84 (t, 2H, (Ex. 5-4 and Ex. 6-15 withProtocol J = 7.3 Hz); 4.05 (s, 3H); 4.11 (q, 2H, J = 7.3 Hz); SX and PA)4.34 (s, 2H); 6.60 (d, 2H, J = 8.5 Hz); 7.02 (d, 2H, J = 8.5 Hz);7.31-7.36 (m, 1H); 7.39-7.50 (m, 4H); 7.80 (d, 1H, J = 2.4 Hz); 8.29 (d,1H, J = 2.4 Hz). 2: Obtaining 3-(4-(((2-methoxy-5- Yield: 57%.Appearance: white solid phenylpyridin-3- ¹H NMR: 2.39 (t, 2H, J = 7.9Hz); 2.63 (t, 2H, J = 7.3 Hz); yl)methyl)amino)phenyl)-propanoic 3.97(s, 3H); 4.22 (d, 2H, J = 5.0 Hz); 6.00 (m, 1H); acid (Protocol SU andPA) 6.51 (d, 2H, J = 8.5 Hz); 6.91 (d, 2H, J = 8.5 Hz); 7.33 (m, 1H);7.43 (m, 2H); 7.54 (d, 2H, J = 7.3 Hz); 7.86 (d, 1H, J = 2.3 Hz); 8.34(d, 1H, J = 2.3 Hz). 42 1: Preparation of ethyl 3-(4-((2- Yield: 75%.Appearance: colorless oil. methoxy-6-phenylpyridin-3- ¹H NMR: 1.11 (t,3H, J = 7.0 Hz); 3.00 (d, 2H, yl)methylamino)phenyl)-3- J = 8.1 Hz);4.03 (q, 2H, J = 7.0 Hz); 4.10 (s, 3H); phenylpropanoate (Ex. 5-1 andEx. 6- 4.31 (s, 2H); 4.45 (t, 1H, J = 8.1 Hz); 6.57 (d, 2H, 14 withProtocol SX and PA) J = 8.6 Hz); 7.05 (d, 2H, J = 8.6 Hz); 7.15-7.32 (m,6H); 7.36-7.49 (m, 4H); 7.60 (d, 1H, J = 7.6 Hz); 8.04 (d, 1H, J = 7.0Hz). 2: Obtaining 3-(4-((2(-methoxy-6- Yield: 36%. Appearance: whitesolid. phenylpyridin-3- ¹H NMR: 2.88 (dd, 2H, J = 7.9 Hz J = 9.4 Hz);4.03 (s, yl)methyl)amino)phenyl)-3-phenyl- 3H); 4.17-4.25 (m, 3H); 6.05(m, 1H); 6.46 (d, 2H, propanoic acid (Protocol SU and PA) J = 8.5 Hz);6.98 (d, 2H, J = 8.5 Hz); 7.08-7.16 (m, 1H); 3: Protocol PC 7.22-7.26(m, 4H); 7.36-7.50 (m, 4H); 7.61 (d, 1H, J = 7.6 Hz); 8.05 (d, 2H, J =7.0 Hz). 43 1: Preparation of ethyl 3-(2-methoxy-4- Yield: 57%.Appearance: yellow oil. ((2-methoxy-6-phenylpyridin-3- ¹H NMR: 1.24 (t,3H, J = 7.3 Hz); 2.55 (m, 2H); yl)methyl-amino)phenyl)propanoate 2.83(m, 2H); 3.76 (s, 3H); 4.08-4.15 (m, 5H); 4.33 (s, (Ex. 5-1 and Ex. 6-22with Protocol SX 2H); 6.17-6.20 (m, 2H); 6.94 (d, 1H, J = 7.6 Hz); andPA) 7.32 (d, 1H, J = 7.3 Hz); 7.36-7.49 (m, 3H); 7.63 (d, 1H, J = 7.6Hz); 8.03-8.06 (m, 2H). 2: Obtaining 3-(2-methoxy-4-(((2- Yield: 44%.Appearance: yellowish solid. methoxy-6-phenylpyridin-3- ¹H NMR: 2.33 (m,2H); 2.60 (m, 2H); 3.67 (s, 3H); yl)methyl)amino)-phenyl)propanoic 4.04(s, 3H); 4.21 (d, 2H, J = 5.0 Hz); 6.00 (dd, 1H, acid (Protocol SU andPA) J = 1.9 Hz J = 8.1 Hz); 6.05 (m, 1H); 6.26 (d, 1H, 3: Protocol PC J= 1.9 Hz); 6.78 (d, 1H, J = 8.1 Hz); 7.37-7.54 (m, 4H); 7.66 (d, 1H, J =7.6 Hz); 8.07 (d, 2H, J = 7.3 Hz); 11.97 (s(l), 1H). 44 1: Preparationof ethyl 3-(3-methoxy-4- Yield: 51%. Appearance: yellow oil.((2-methoxy-6-phenylpyridin-3- ¹H NMR: 1.25 (t, 3H, J = 7.1 Hz); 2.58(m, 2H); yl)methyl-amino)phenyl)propanoate 2.87 (m, 2H); 3.88 (s, 3H);4.11 (s, 3H); 4.12 (q, 2H, (Ex. 5-1 and Ex. 6-23 with Protocol SX J =7.1 Hz); 4.35 (s, 2H); 6.48 (d, 1H, J = 8.2 Hz); and PA) 6.64-6.67 (m,2H); 7.30 (d, 1H, J = 7.6 Hz); 7.35-7.48 (m, 3H); 7.60 (d, 1H, J = 7.3Hz); 8.02-8.05 (m, 2H). 2: Obtaining 3-(3-methoxy-4-(((2- Yield: 46%.Appearance: white solid. methoxy-6-phenylpyridin-3- ¹H NMR: 2.44 (t, 2H,J = 7.9 Hz); 2.67 (t, 2H, yl)methyl)amino)-phenyl)propanoic J = 7.9 Hz);3.80 (s, 3H); 4.04 (s, 3H); 4.26 (m, 2H); acid (Protocol SU and PA) 5.36(m, 1H); 6.26 (d, 1H, J = 8.1 Hz); 6.53 (dd, 1H, 3: Protocol PC J = 1.4Hz J = 8.1 Hz); 6.71 (d, 1H, J = 1.4 Hz); 7.36-7.50 (m, 4H); 7.56 (d,1H, J = 7.6 Hz); 8.06 (d, 2H, J = 7.7 Hz); 12.01 (s, 1H). 45 1:Preparation of ethyl 3-(4-((2- Yield: 56%. Appearance: yellow oil;methoxy-6-phenylpyridin-3- ¹H NMR: 1.19 (t, 3H, J = 7.2 Hz); 1.26 (d,3H, yl)methylamino)-phenyl)butanoate (Ex. J = 7.0 Hz); 2.43-2.60 (m,2H); 3.14-3.22 (m, 1H); 5-1 and Ex. 6-24 with Protocol SX and 4.08 (q,2H, J = 7.2 Hz); 4.11 (s, 3H); 4.33 (s, 2H); PA) 6.60 (d, 2H, J = 8.5Hz); 7.03 (d, 2H, J = 8.5 Hz); 7.31 (d, 1H, J = 7.3 Hz); 7.36-7.49 (m,3H); 7.62 (d, 1H, J = 7.6 Hz); 8.04 (d, 2H, J = 8.5 Hz). 2: Obtaining3-(4-(((2-methoxy-6- Yield: 52%; Appearance: white solid.phenylpyridin-3- ¹H NMR: 1.12 (d, 3H, J = 6.7 Hz); 2.37 (m, 2H);yl)methyl)amino)phenyl)butanoic acid 2.93-3.00 (m, 1H); 4.04 (s, 3H);4.20 (d, 2H, J = 4.4 Hz); (Protocol SU and PA) 6.00 (m, 1H); 6.48 (d,2H, J = 8.2 Hz); 6.93 (d, 2H, 3: Protocol PC J = 8.2 Hz); 7.37-7.53 (m,4H); 7.63 (d, 1H, J = 7.6 Hz); 8.06 (d, 2H, J = 7.3 Hz); 11.93 (s, 1H).46 1: Preparation of ethyl 3-(4-((2- Yield: 74%. Appearance: yellow oil.methoxy-5-(4- ¹H NMR: 1.22 (t, 3H, J = 7.0 Hz); 2.55 (m, 2H);(trifluoromethyl)phenyl)pyridin-3- 2.84 (m, 2H); 4.06 (s, 3H); 4.11 (q,2H, J = 7.0 Hz); yl)methylamino)phenyl)propanoate 4.36 (s, 2H); 6.62 (d,2H, J = 8.5 Hz); 7.02 (d, 2H, (Ex. 5-12 and Ex. 6-15 with Protocol J =8.5 Hz); 7.58 (d, 2H, J = 8.2 Hz); 7.67 (d, 2H, SX and PA) J = 8.2 Hz);7.81 (d, 1H, J = 2.3 Hz); 8.30 (d, 1H, J = 2.3 Hz). 2: Obtaining3-(4-(((2-methoxy-5-(4- Yield: 44%. Appearance: white solid.(trifluoromethyl) phenyl)pyridin-3- ¹H NMR: 2.39 (t, 2H, J = 7.6 Hz);2.63 (t, 2H, yl)methyl) amino) phenyl)propanoic J = 7.6 Hz); 3.99 (s,3H); 4.23 (d, 2H, J = 5.7 Hz); acid (Protocol SU and PA) 5.99 (t, 1H, J= 5.7 Hz); 6.51 (d, 2H, J = 8.4 Hz); 6.91 (d, 2H, 3: Protocol PC J = 8.4Hz); 7.75-7.82 (m, 4H); 7.95 (d, 1H, J = 2.5 Hz); 8.44 (d, 1H, J = 2.5Hz); 12.00 (s, 1H). 47 1: Preparation of ethyl 3-(4-((2- Yield: 65%.Appearance: yellow oil. methoxy-5-(3- ¹H NMR: 1.22 (t, 3H, J = 7.0 Hz);2.55 (m, 2H); (trifluoromethyl)phenyl)pyridin-3- 2.84 (m, 2H); 4.06 (s,3H); 4.11 (q, 2H, J = 7.0 Hz); yl)methylamino)-phenyl)propanoate 4.36(s, 2H); 6.60 (d, 2H, J = 8.5 Hz); 7.02 (d, 2H, (Ex. 5-13 and Ex. 6-15with Protocol J = 8.5 Hz); 7.51-7.66 (m, 3H); 7.70 (s, 1H); 7.79 (d, SXand PA) 1H, J = 2.5 Hz); 8.29 (d, 1H, J = 2.5 Hz). 2: Obtaining3-(4-(((2-methoxy-5-(3- Yield: 52%. Appearance: white solid.(trifluoromethyl) phenyl) pyridin-3- ¹H NMR: 2.39 (m, 2H); 2.63 (m, 2H);3.98 (s, 3H); yl)methyl)amino)-phenyl) propanoic 4.23 (d, 2H, J = 5.7Hz); 5.98 (t, 1H, J = 5.7 Hz); acid (Protocol SU and PA) 6.52 (d, 2H, J= 8.3 Hz); 6.91 (d, 2H, J = 8.3 Hz); 3: Protocol PC 7.67-7.69 (m, 2H);7.85-7.89 (m, 2H); 7.96 (d, 1H, J = 2.3 Hz); 8.44 (d, 1H, J = 2.3 Hz);11.98 (s, 1H). 48 1: Preparation of ethyl 3-(4-((2,6- Yield: 48%.Appearance: colorless oil. dimethoxy-5-phenylpyridin-3- ¹H NMR: 1.23 (t,3H, J = 7.0 Hz); 2.56 (t, 2H, yl)methylamino)-phenyl)propanoate J = 7.3Hz); 2.84 (t, 2H, J = 7.3 Hz); 3.97 (s, 3H); (Ex. 5-14 and Ex. 6-15 withProtocol 4.00 (s, 3H); 4.12 (q, 2H, J = 7.0 Hz); 4.25 (s, 2H); 6.61 (d,SX and PA) 2H, J = 8.5 Hz); 7.01 (d, 2H, J = 8.5 Hz); 7.28-7.31 (m, 1H);7.36-7.41 (m, 2H); 7.50 (m, 2H); 7.58 (s, 1H). 2: Obtaining3-(4-(((2,6-dimethoxy-5- Yield: 46%. Appearance: beige solid.phenylpyridin-3- ¹H NMR: 2.39 (t, 2H, J = 7.6 Hz); 2.62 (t, 2H,yl)methyl)amino)phenyl)-propanoic J = 7.6 Hz); 3.90 (s, 3H); 3.99 (s,3H); 4.13 (d, 2H, acid J = 5.7 Hz); 5.87 (t, 1H, J = 5.7 Hz); 6.49 (d,2H, (Protocol SU and PA) J = 8.2 Hz); 6.89 (d, 2H, J = 8.2 Hz);7.24-7.29 (m, 1H); 3: Protocol PC 7.34-7.44 (m, 4H); 7.62 (s, 1H); 12.05(s, 1H). 49 1: Preparation of ethyl 3-(4-((5-(4- Yield: 68%. Appearance:colorless oil. chlorophenyl)-2-methoxypyridin-3- ¹H NMR: 1.22 (t, 3H, J= 7.2 Hz); 2.55 (m, 2H); yl)methyl-amino)phenyl)propanoate 2.84 (m, 2H);4.05 (s, 3H); 4.11 (q, 2H, J = 7.2 Hz); (Ex. 5-15 and Ex. 6-15 withProtocol 4.34 (s, 2H); 6.58 (d, 2H, J = 8.5 Hz); 7.01 (d, 2H, SX and PA)J = 8.5 Hz); 7.39 (m, 4H); 7.75 (d, 1H, J = 2.5 Hz); 8.25 (d, 1H, J =2.5 Hz). 2: Obtaining 3-(4-(((5-(4-chlorophenyl)- Yield: 32%.Appearance: white solid. 2-methoxypyridin-3- ¹H NMR: 2.62 (m, 2H); 2.85(m, 2H); 4.05 (s, 3H); yl)methyl)amino)phenyl)-propanoic 4.33 (s, 2H);6.59 (d, 2H, J = 8.4 Hz); 7.02 (d, 2H, acid (Protocol SU and PC) J = 8.4Hz); 7.38 (m, 4H); 7.75 (d, 1H, J = 2.4 Hz); 8.25 (d, 1H, J = 2.4 Hz).50 1: Preparation of ethyl 3-(4-((2- Yield: 80%. Appearance: colorlessoil. methoxy-5-(naphthalen-2- ¹H NMR: 1.20 (t, 3H, J = 7.2 Hz); 2.56 (m,2H); 2.84 (m, yl)pyridin-3-yl)methyl- 2H); 4.08 (s, 3H); 4.10 (q, 2H, J= 7.2 Hz); 4.38 (s, 2H); amino)phenyl)propanoate (Ex. 5- 6.64 (d, 2H, J= 8.4 Hz); 7.03 (d, 2H, J = 8.4 Hz); 16 and Ex. 6-15 with Protocol SX7.45-7.54 (m, 2H); 7.62 (dd, 1H, J = 1.8 Hz J = 8.5 Hz); 7.84-7.93 (m,and PA) 5H); 8.41 (d, 1H, J = 2.4 Hz). 2: Obtaining 3-(4-(((2-methoxy-5-Yield: 53%. Appearance: white solid. (naphthalen-2-yl)pyridin-3- ¹H NMR:2.40 (m, 2H); 2.63 (m, 2H); 4.00 (s, 3H); yl)methyl) amino)phenyl)- 4.25(m, 2H); 6.02 (m, 1H); 6.53 (d, 2H, J = 8.5 Hz); 6.92 (d, propanoic acid(Protocol SU and 2H, J = 8.5 Hz); 7.47-7.55 (m, 2H); 7.72 (dd, 1H, J =1.5 Hz PC) J = 8.5 Hz), 7.90-8.09 (m, 5H); 8.50 (d, 1H, J = 2.3 Hz);11.99 (s, 1H). 51 1: Preparation of ethyl 3-(4-((2- Yield: 49%.Appearance: colorless oil. ethoxy-6-phenylpyridin-3-yl)methylamino)- ¹HNMR: 1.24 (t, 3H, J = 7.1 Hz); 1.47 (t, 3H, J = 7.0 Hz);phenyl)propanoate 2.56 (m, 2H); 2.84 (m, 2H); 4.12 (q, 2H, J = 7.1 Hz);(Ex. 5-17 and Ex. 6-15 with 4.33 (s, 2H); 4.58 (q, 2H, J = 7.0 Hz); 6.60(d, 2H, J = 8.5 Hz); Protocol SX and PA) 7.02 (d, 2H, J = 8.5 Hz);7.27-7.30 (m, 1H); 7.35-7.48 (m, 3H); 7.60 (d, 1H, J = 7.6 Hz);8.00-8.03 (m, 2H). 2: Obtaining 3-(4-(((2-ethoxy-6- Yield: 77%.Appearance: white solid. phenylpyridin-3- ¹H NMR: 1.41 (t, 3H, J = 7.0Hz); 2.41 (m, 2H); 2.64 (m, yl)methyl)amino)phenyl)propanoic 2H); 4.20(s, 2H); 4.52 (q, 2H, J = 7.0 Hz); 5.99 (s, 1H); acid (Protocol SU andPA) 6.48 (d, 2H, J = 8.2 Hz); 6.91 (d, 2H, J = 8.2 Hz); 3: Protocol PC7.36-7.50 (m, 4H); 7.62 (d, 1H, J = 7.6 Hz); 8.04 (d, 2H, J = 7.3 Hz);12.01 (s, 1H). 54 1: Preparation of ethyl 3-(4-((2- Yield: 65%.Appearance: colorless oil. isopropoxy-6-phenylpyridin-3- ¹H NMR: 1.24(t, 3H, J = 7.1 Hz); 1.44 (s, 3H); 1.46 (s, 3H);yl)methylamino)-phenyl)propanoate 2.57 (m, 2H); 2.84 (m, 2H); 4.13 (q,2H, J = 7.1 Hz); (Ex. 5-18 and Ex. 6- 4.31 (s, 2H); 5.55-5.63 (m, 1H);6.59 (d, 2H, J = 8.5 Hz); 15 with Protocol SX and PA) 7.02 (d, 2H, J =8.5 Hz); 7.27 (d, 1H, J = 7.6 Hz); 7.35-7.47 (m, 3H); 7.59 (d, 1H, J =7.6 Hz); 8.01 (m, 2H). 2: Obtaining 3-(4-(((2- Yield: 75%. Appearance:white solid. isopropyloxy-6-phenylpyridin-3- ¹H NMR: 1.39 (s, 3H); 1.41(s, 3H); 2.41 (m, 2H); yl)methyl)amino)phenyl)- 2.64 (m, 2H); 4.17 (s,2H); 5.44-5.52 (m, 1H); 5.97 (m, 1H); propanoic acid (Protocol SU and6.48 (d, 2H, J = 8.4 Hz); 6.92 (d, 2H, J = 8.4 Hz); PA) 7.35-7.47 (m,4H); 7.62 (d, 1H, J = 7.6 Hz); 8.02 (d, 2H, J = 7.0 Hz); 3: Protocol PC12.01 (s, 1H).

Synthesis of the compounds according to the invention in FIGS. 7 b and 7c requires 2 stages and is summarized in Table 7-2.

TABLE 7-2 Cpd No. and type of Stage (Ex.; Protocol) Details 13 1:Preparation of tert-butyl 2-(3-((2- Yield: 49%. Appearance: yellow oil.methoxy-6-phenylpyridin-3- ¹H NMR: 1.45 (s, 9H); 1.55 (s, 6H); 4.11 (s,3H); yl)methylamino)phenoxy)-2-methyl- 4.18 (s, 1H); 4.31 (s, 2H);6.20-6.31 (m, 3H); propanoate (Ex. 5-1 and Ex. 6-12 with 7.01 (m, 1H);7.31 (d, 1H, J = 7.6 Hz); 7.37-7.49 (m, 3H); Protocol SX and PA) 7.61(d, 1H, J = 7.6 Hz); 8.05 (d, 2H, J = 8.8 Hz). 2: Obtaining2-(3-(((2-methoxy-6- Yield: 33%. Appearance: white solid.phenylpyridin-3- ¹H NMR: 1.42 (s, 6H); 4.17 (d, 2H, J = 5.5 Hz);yl)methyl)amino)phenoxy)-2-methyl- 5.98-6.02 (m, 2H); 6.16-6.20 (m, 2H);6.90 (t, 1H, propanoic acid (Protocol SU and PB) J = 7.9 Hz); 7.37-7.53(m, 4H); 7.62 (d, 1H, J = 7.6 Hz); 8.07 (d, 2H, J = 7.3 Hz). 14 1:Preparation of tert-butyl 2-(3-((2- Yield: 80%. Appearance: yellow oil.methoxy-6-phenylpyridin-3- ¹H NMR: 1.49 (s, 9H); 4.12 (s, 3H); 4.33 (s,2H); yl)methylamino)-phenoxy)ethanoate 4.47 (s, 2H); 6.22-6.33 (m, 3H);7.08 (t, 1H, (Ex. 5-1 and Ex. 6-13 with Protocol SX J = 7.6 Hz); 7.31(d, 1H, J = 7.6 Hz); 7.37-7.49 (m, and PA) 3H); 7.61 (d, 1H, J = 7.6Hz); 8.05 (d, 2H, J = 7.0 Hz). 2: Obtaining 2-(3-(((2-methoxy-6- Yield:60%. Appearance: white solid. phenylpyridin-3- ¹H NMR: 4.12 (s, 3H);4.34 (s, 2H); 4.61 (s, 2H); yl)methyl)amino)phenoxy) ethanoic 6.24-6.37(m, 3H); 7.09 (m, 1H); 7.31 (d, 1H, acid (Protocol SU and PB) J = 7.6Hz); 7.36-7.48 (m, 3H); 7.60 (d, 1H, J = 7.6 Hz); 8.04 (d, 2H, J = 6.7Hz). 34 1: Preparation of ethyl 3-(4-(1-(2- Yield: 14%. Appearance:yellow oil methoxy-6-phenylpyridin-3- yl)propylamino)-phenyl)propanoate(Ex. 5-8 and Ex. 6-15 with Protocol SY and PA) 2: Obtaining3-(4-(1-((2-methoxy-6- Yield: 58%. Appearance: white solid.phenylpyridin-3- ¹H NMR: 0.94 (t, 3H, J = 7.3 Hz); 1.65-1.78 (m, 2H);yl)propyl)amino)phenyl)-propanoic acid 2.35 (t, 2H, J = 7.3 Hz); 2.58(t, 2H, J = 7.3 Hz); (Protocol SU and PB) 4.06 (s, 3H); 4.46 (m, 1H);5.96 (d, 1H, J = 7.9 Hz); 6.39 (d, 2H, J = 8.5 Hz); 6.83 (d, 2H, J = 8.5Hz); 7.36-7.51 (m, 4H); 7.66 (d, 1H, J = 7.9 Hz); 8.06 (d, 2H; J = 7.0Hz).

Synthesis of the compounds according to the invention in FIG. 7 drequires 2 or 3 stages and is summarized in Table 7-3.

TABLE 7-3 No. and type of Stage (Ex.; Cpd Protocol) Details 2 1:Preparation of tert-butyl 2-(4-((2- Yield: 54%. Appearance: white solid.methoxy-6-phenylpyridin-3- ¹H NMR: 1.47 (s, 9H); 4.11 (s, 3H); 4.59 (s,2H); yl)methoxy)phenoxy)-ethanoate (Ex. 5.02 (s, 2H); 6.88 (d, 2H, J =9.1 Hz); 6.95 (d, 2H, 4-1 and Ex. 6-2 with Protocol SV and J = 9.1 Hz);7.34-7.49 (m, 4H); 7.76 (d, 1H, J = 7.6 Hz); PA) 8.02 (m, 2H). 2:Obtaining 2-(4-((2-methoxy-6- Yield: 83%. Appearance: white solid.phenylpyridin-3- ¹H NMR: 4.03 (s, 3H); 4.60 (s, 2H); 5.03 (s, 2H);yl)methoxy)phenoxy)ethanoic acid 6.84 (d, 2H, J = 9.1 Hz); 6.96 (d, 2H,J = 9.1 Hz); (Protocol SW and PE) 7.40-7.55 (m, 3H); 7.58 (d, 1H, J =7.6 Hz); 7.84 (d, 1H, J = 7.6 Hz); 8.10 (d, 2H, J = 7.0 Hz); 12.83 (s(broad), 1H). 6 1: Preparation of ethyl 2-(4-((2-tert- Yield: 33%.Appearance: yellow oil. butoxy-6-phenylpyridin-3- ¹H NMR: 1.29 (t, 3H, J= 7.2 Hz); 1.57 (s, 6H); 1.71 (s, yl)methoxy)phenoxy)-2-methyl- 9H);4.26 (q, 2H, J = 7.2 Hz); 5.02 (s, 2H); propanoate (Ex. 4-2 and Ex. 6-1with 6.85-6.92 (m, 4H); 7.34-7.50 (m, 4H); 7.76 (d, 1H, J = 7.6 Hz);Protocol SV and PA) 8.03 (d, 2H, J = 7.3 Hz). 2: Obtaining2-(4-((2-tert-butyloxy-6- Yield: 67%. Appearance: white solid.phenylpyridin-3- ¹H NMR: 1.44 (s, 6H); 1.63 (s, 9H); 4.97 (s, 2H);yl)methoxy)phenoxy)-2-methyl- 6.83 (d, 2H, J = 9.1 Hz); 6.93 (d, 2H, J =9.1 Hz); propanoic acid (Protocol SU and PD) 7.42-7.57 (m, 4H); 7.80 (d,1H, J = 7.6 Hz); 8.03 (d, 2H, J = 7.3 Hz); 12.94 (s, 1H). 7 1:Preparation of ethyl 2-(4-((2-tert- Yield: 80%. Appearance: white solid.butoxy-6-phenylpyridin-3- ¹H NMR: 1.32 (t, 3H, J = 7.2 Hz); 1.71 (s,9H); 4.29 (q, yl)methoxy)phenoxy)ethanoate (Ex. 2H, J = 7.2 Hz); 4.59(s, 2H); 5.02 (s, 2H); 6.88 (d, 4-2 and Ex. 6-4 with Protocol SV and 2H,J = 9.2 Hz); 6.95 (d, 2H, J = 9.2 Hz); 7.34-7.49 (m, PA) 4H); 7.76 (d,1H, J = 7.6 Hz); 8.02 (d, 2H, J = 7.3 Hz). 2: Obtaining2-(4-(((2-tert-butyloxy-6- Yield: 33%. Appearance: white solid.phenylpyridin-3-yl)methoxy)phenoxy)ethanoic ¹H NMR: 1.64 (s, 9H); 4.59(s, 2H); 4.97 (s, 2H); acid (Protocol SU and PD) 6.85 (d, 2H, J = 9.1Hz); 6.94 (d, 2H, J = 9.1 Hz); 7.39-7.56 (m, 4H); 7.79 (d, 1H, J = 7.6Hz); 8.03 (d, 2H, J = 7.3 Hz); 12.94 (s, 1H). 15 1: Preparation oftert-butyl 2-(4-((2- Yield: 39%. Appearance: yellow oil.hexyloxy-6-phenylpyridin-3- ¹H NMR: 0.91 (t, 3H, J = 7.0 Hz); 1.26-1.55(m, 6H); yl)methoxy)-phenoxy)ethanoate (Ex. 1.49 (s, 9H); 1.84 (m, 2H);4.47 (s, 2H); 4.51 (t, 2H, 4-3 and Ex. 6-2 with Protocol SV and J = 6.5Hz); 5.06 (s, 2H); 6.85 (d, 2H, J = 9.4 Hz); PA) 6.94 (d, 2H, J = 9.4Hz); 7.34-7.48 (m, 4H); 7.77 (d, 1H, J = 7.6 Hz); 8.03 (d, 2H, J = 7.0Hz). 2: Obtaining 2-(4-((2-hexyloxy-6- Yield: 31%. Appearance: whitesolid. phenylpyridin-3- ¹H NMR: 0.91 (t, 3H, J = 6.7 Hz); 1.34-1.49 (m,6H); yl)methoxy)phenoxy)ethanoic acid 1.79-1.88 (m, 2H); 4.51 (t, 2H, J= 6.7 Hz); 4.63 (s, (Protocol SW and PA) 2H); 5.07 (s, 2H); 6.89 (d, 2H,J = 9.2 Hz); 6.95 (d, 3: Protocol PC 2H, J = 9.2 Hz); 7.34-7.48 (m, 4H);7.76 (d, 1H, J = 7.6 Hz); 8.03 (d, 2H, J = 7.2 Hz). 17 1: Preparation oftert-butyl 2-(4-((2- Yield: 37%; Appearance: yellow oil.hexyloxy-6-phenylpyridin-3- ¹H NMR: 0.91 (t, 3H, J = 7.0 Hz); 1.30-1.46(m, 6H); yl)methoxy)-phenoxy)-2-methyl- 1.46 (s, 9H); 1.52 (s, 6H); 1.83(m, 2H); 4.51 (t, 2H, propanoate (Ex. 4-3 and Ex. 6-5 with J = 6.4 Hz);5.06 (s, 2H); 6.87 (m, 4H); 7.35-7.49 (m, Protocol SV and PA) 4H); 7.78(d, 1H, J = 7.6 Hz); 8.03 (d, 2H, J = 7.9 Hz). 2: Obtaining2-(4-((2-hexyloxy-6- Yield: 26%; Appearance: white solid.phenylpyridin-3- ¹H NMR: 0.91 (t, 3H, J = 7.0 Hz); 1.26-1.56 (m, 12H);yl)methoxy)phenoxy)-2-methyl- 1.79-1.89 (m, 2H); 4.52 (t, 2H, J = 6.7Hz); 5.08 (s, propanoic acid (Protocol SW and PB) 2H); 6.94 (m, 4H);7.35-7.48 (m, 4H); 7.78 (d, 1H, J = 7.6 Hz); 8.04 (d, 2H, J = 8.5 Hz).18 1: Preparation of tert-butyl 2-(4-((2- Yield: 39%. Appearance: yellowoil. cyclohexyloxy-6-phenylpyridin-3- ¹H NMR: 1.50 (s, 9H); 1.50-1.72(m, 6H); yl)methoxy)-phenoxy)ethanoate (Ex. 1.80-1.83 (m, 2H); 2.03-2.04(m, 2H); 4.48 (s, 2H); 5.07 (s, 4-4 and Ex. 6-2 with Protocol SV and2H); 5.33 (m, 1H); 6.88 (d, 2H, J = 9.2 Hz); 6.95 (d, PA) 2H, J = 9.2Hz); 7.34 (d, 1H, J = 7.6 Hz); 7.36-7.49 (d, 3H); 7.78 (d, 1H, J = 7.6Hz); 8.02 (d, 2H, J = 8.5 Hz). 2: Obtaining 2-(4-((2-cyclohexyloxy-Yield: 16%. Appearance: white solid. 6-phenylpyridin-3- ¹H NMR:1.26-2.03 (m, 10H); 4.64 (s, 2H); 5.07 (s, yl)methoxy)phenoxy)ethanoicacid 2H); 5.32-5.36 (m, 1H); 6.88-6.99 (m, 4H); (Protocol SW and PB)7.32-7.48 (m, 4H); 7.76 (d, 1H, J = 7.6 Hz); 8.01 (d, 2H, J = 7.0 Hz).20 1: Preparation of ethyl 2-(4-((6- Yield: 60%. Appearance: whitesolid. phenyl-2-(piperidin-1-yl)pyridin-3- ¹H NMR: 0.84 (m, 3H);1.34-1.76 (m, 6H); 3.27 (m, yl)methoxy)-phenoxy)ethanoate (Ex. 4H); 4.27(q, 2H, J = 7.0 Hz); 4.57 (s, 2H); 5.07 (s, 4-5 and Ex. 6-4 withProtocol SV and 2H); 6.85-6.94 (m, 4H); 7.39-7.48 (m, 4H); PA) 7.82-7.86(m, 1H); 8.05 (d, 2H, J = 6.7 Hz). 2: Obtaining 2-(4-((6-phenyl-2-Yield: 21%. Appearance: white solid. (piperidin-1-yl)pyridin-3- ¹H NMR:1.59-1.67 (m, 6H); 3.17 (m, 4H); 4.49 (s, yl)methoxy)phenoxy)-ethanoicacid 2H); 5.00 (s, 2H); 6.82 (d, 2H, J = 9.2 Hz); 6.92 (d, (Protocol SUand PB) 2H, J = 9.2 Hz); 7.37-7.49 (m, 3H); 7.57 (d, 1H, J = 7.7 Hz);7.82 (d, 1H, J = 7.7 Hz); 8.07 (d, 2H, J = 7.0 Hz). 21 1: Preparation oftert-butyl 2-(4-((2- Yield: 47%; Appearance: white solid. methoxy-6-(4-¹H NMR: 1.47 (s, 9H); 1.53 (s, 6H); 4.09 (s, 3H);(trifluoromethyl)phenyl)pyridin-3- 5.07 (s, 2H); 6.85-6.92 (m, 4H); 7.43(d, 1H, yl)methoxy)-phenoxy)-2-methyl J = 7.6 Hz); 7.72 (d, 2H, J = 8.2Hz); 7.84 (d, 1H, propanoate (Ex. 4-6 and Ex. 6-5 with J = 7.6 Hz); 8.17(d, 2H, J = 8.2 Hz). Protocol SV and PA) 2: Obtaining2-(4-((2-methoxy-6-(4- Yield: 34%. Appearance: white solid.(trifluoromethyl) phenyl) pyridin-3- ¹H NMR: 1.56 (s, 6H); 4.12 (s, 3H);5.19 (s, 2H); yl)methoxy)-phenoxy)-2- 6.95 (s, 4H); 7.43 (d, 1H, J = 7.6Hz); 7.72 (d, 2H, methylpropanoic acid (Protocol SW J = 8.2 Hz); 7.84(d, 1H, J = 7.6 Hz); 8.17 (d, 2H, and PA) J = 8.2 Hz). 3: Protocol PC 241: Preparation of tert-butyl 2-(4-((2- Yield: 53%. Appearance: whitesolid. methoxy-6-(4- ¹H NMR: 1.50 (s, 9H); 4.11 (s, 3H); 4.48 (s, 2H);(trifluoromethyl)phenyl)pyridin-3- 5.07 (s, 2H); 6.58-6.96 (m, 4H); 7.42(d, 1H, yl)methoxy)phenoxy)ethanoate (Ex. 4-6 J = 7.6 Hz); 7.71 (d, 2H,J = 8.2 Hz); 7.83 (d, 1H, and Ex. 6-2 with Protocol SV and J = 7.6 Hz);8.16 (d, 2H, J = 8.2 Hz). PA) 2: Obtaining 2-(4-((2-methoxy-6-(4- Yield:12%. Appearance: white solid. (trifluoromethyl)phenyl)pyridin-3- ¹H NMR:4.12 (s, 3H); 4.64 (s, 2H); 5.09 (s, 2H); yl)methoxy)-phenoxy)ethanoicacid 6.92-6.96 (m, 4H); 7.42 (d, 1H, J = 7.6 Hz); 7.71 (d, (Protocol SWand PA) 2H, J = 8.2 Hz); 7.82 (d, 1H, J = 7.6 Hz); 8.17 (d, 2H, 3:Protocol PC J = 8.2 Hz). 25 1: Preparation of ethyl 2-(4-((2- Yield:27%. Appearance: white solid. phenylthio-6-(phenyl)pyridin-3- ¹H NMR:1.31 (t, 3H, J = 7.2 Hz); 4.28 (q, 2H, yl)methoxy)-phenoxy)ethanoate(Ex. 4-7 J = 7.2 Hz); 4.59 (s, 2H); 5.14 (s, 2H); 6.89 (d, 2H, and Ex.6-4 with Protocol SV and J = 9.4 Hz); 6.96 (d, 2H, J = 9.4 Hz);7.32-7.35 (m, PA) 3H); 7.40-7.45 (m, 3H); 7.56 (d, 1H, J = 7.9 Hz);7.60-7.63 (m, 2H); 7.75-7.81 (m, 3H). 2: Obtaining2-(4-((2-phenylthio-6- Yield: 71%; Appearance: white solid(phenyl)pyridin-3- ¹H NMR: 4.65 (s, 2H); 5.15 (s, 2H); 6.91 (d, 2H,yl)methoxy)phenoxy)ethanoic acid J = 9.2 Hz); 6.98 (d, 2H, J = 9.2 Hz);7.33-7.35 (m, (Protocol SU and PD) 3H); 7.40-7.45 (m, 3H); 7.56 (d, 1H,J = 8.2 Hz); 7.59-7.63 (m, 2H); 7.74-7.81 (m, 3H). 52 1: Preparation ofethyl 3-(4-((2- Yield: 18%; Appearance: yellow oil.methoxy-5-phenylpyridin-3- ¹H NMR: 1.22 (t, 3H, J = 7.3 Hz); 1.84 (d,3H, yl)methoxy)phenyl)-hex-4-ynoate (Ex. J = 2.3 Hz); 2.66 (dd, 1H, J =7.0 Hz, J = 14.9 Hz); 4-8 and Ex. 6-25 with Protocol SV and 2.76 (dd,1H, J = 8.2 Hz, J = 14.9 Hz); 4.05-4.18 (m, 6H); PA) 5.10 (s, 2H); 6.96(d, 2H, J = 8.8 Hz); 7.30-7.39 (m, 3H); 7.42-7.47 (m, 2H); 7.53-7.56 (m,2H); 7.98 (d, 1H, J = 2.3 Hz); 7.34 (d, 1H, J = 2.3 Hz). 2: Obtaining3-(4-((2-methoxy-5- Yield: 26%. Appearance: white solid.phenylpyridin-3- ¹H NMR (300 MHz, DMSO d₆, □ in ppm): 1.77 (s,yl)methoxy)phenyl)hex-4-ynoic acid 3H); 2.59 (d, 2H, J = 7.6 Hz); 3.96(m, 4H); 5.07 (s, (Protocol SU and PB) 2H); 6.99 (d, 2H, J = 8.5 Hz);7.29 (d, 2H, J = 8.5 Hz); 7.34-7.39 (m, 1H); 7.47 (m, 2H); 7.65 (d, 2H,J = 7.6 Hz); 8.08 (d, 1H, J = 1.8 Hz); 8.47 (d, 1H, J = 1.8 Hz); 12.24(s, 1H). 53 1: Preparation of ethyl 3-(4-((2- Yield: 36%. Appearance:colorless oil. methoxy-6-phenylpyridin-3- ¹H NMR: 1.23 (t, 3H, J = 7.0Hz); 1.84 (d, 3H, yl)methoxy)phenyl)-hex-4-ynoate (Ex. J = 2.3 Hz); 2.66(dd, 1H, J = 7.0 Hz, J = 14.9 Hz); 4-1 and Ex. 6-25 with Protocol SV and2.76 (dd, 1H, J = 8.2 Hz, J = 14.9 Hz); 4.07-4.18 (m, 6H); PA) 5.10 (s,2H); 6.95 (d, 2H, J = 8.5 Hz); 7.31 (d, 2H, J = 8.5 Hz); 7.37-7.50 (m,4H); 7.78 (d, 1H, J = 7.6 Hz); 8.04-8.08 (m, 2H). 2: Obtaining3-(4-((2-methoxy-6- Yield: 42%. Appearance: white solid.phenylpyridin-3- ¹H NMR: 2.39 (d, 3H, J = 2.3 Hz); 3.21 (d, 2H,yl)methoxy)phenyl)hex-4-ynoic acid J = 7.6 Hz); 4.54-4.59 (m, 1H); 4.65(s, 3H); 5.68 (s, (Protocol SU and PA) 2H); 7.58 (d, 2H, J = 8.8 Hz);7.90 (d, 2H, J = 8.8 Hz); 3: Protocol PC 8.01-8.13 (m, 3H); 8.21 (d, 1H,J = 7.6 Hz); 8.46 (d, 1H, J = 7.6 Hz); 8.71-8.74 (m, 2H); 12.88 (s, 1H).

Synthesis of the compounds according to the invention in FIGS. 7 e and 7f requires 1 or 2 stages and is summarized in Table 7-4.

TABLE 7-4 Cpd No. and type of Stage (Ex.; Protocol) Details 1 1:Preparation of ethyl 2-(4-((2- Yield: 47%. Appearance: colorless oil.methoxy-6-phenylpyridin-3- ¹H NMR: 1.30 (t, 3H, J = 7.0 Hz); 1.57 (s,6H); yl)methoxy)phenoxy)-2-methyl- 4.12 (s, 3H); 4.26 (q, 2H, J = 7.0Hz); 5.07 (s, 2H); propanoate (Ex. 4-15 and Ex. 6-1 with 6.85-6.92 (m,4H); 7.38-7.50 (m, 4H); 7.80 (d, Protocol SQ and PA) 1H, J = 7.6 Hz);8.07 (d, 2H, J = 7.3 Hz). 2: Obtaining 2-(4-((2-methoxy-6- Yield: 20%.Appearance: white solid. phenylpyridin-3-yl)methoxy)phenoxy)- ¹H NMR:1.57 (s, 6H); 4.12 (s, 3H); 5.09 (s, 2H); 2-methyl-propanoic acid(Protocol SU 6.94 (s, 4H); 7.38-7.50 (m, 4H); 7.79 (d, 1H, and PA) J =7.6 Hz); 8.06 (d, 2H, J = 7.3 Hz). 3 1: Preparation of ethyl 2-(4-((2-Yield: quantitative. Appearance: white solid. methoxy-6-phenylpyridin-3-¹H NMR: 1.27 (t, 3H, J = 7.0 Hz); 1.62 (m, 3H);yl)methoxy)phenoxy)-propanoate (Ex. 4.11 (s, 3H); 4.23 (q, 2H, J = 7.0Hz); 4-15 and Ex. 6-3 with Protocol SQ and 4.64-4.71 (m, 1H); 5.06 (s,2H); 6.85 (d, 2H, J = 9.3 Hz); PA) 6.93 (d, 2H, J = 9.3 Hz); 7.38-7.50(m, 4H); 7.79 (d, 1H, J = 7.6 Hz); 8.06 (d, 2H, J = 7.3 Hz). 2:Obtaining 2-(4-((2-methoxy-6- Yield: 29%. Appearance: white solid.phenylpyridin-3- ¹H NMR: 1.35 (d, 3H, J = 6.4 Hz); 4.02 (s, 3H);yl)methoxy)phenoxy)propanoic acid 4.24 (m, 1H); 4.99 (s, 2H); 6.73 (d,2H, (Protocol SU and PD) J = 8.8 Hz); 6.87 (d, 2H, J = 8.8 Hz);7.40-7.51 (m, 3H); 7.59 (d, 1H, J = 7.6 Hz); 7.82 (d, 1H, J = 7.6 Hz);8.10 (d, 2H, J = 7.6 Hz). 5 1: Preparation of ethyl 2-(4-((2- Yield:20%. Appearance: yellow oil. methoxy-6-phenylpyridin-3- ¹H NMR: 1.27 (t,3H, J = 7.1 Hz); 1.59 (d, 3H, yl)methylamino)phenoxy)propanoate J = 6.8Hz); 4.11 (s, 3H); 4.22 (q, 2H, J = 7.1 Hz); (Ex. 4-16 and Ex. 6-7 withProtocol SQ 4.30 (s, 2H); 4.62 (q, 1H, J = 6.8 Hz); 6.61 (d, 2H, and PA)J = 9.0 Hz); 6.79 (d, 2H, J = 9.0 Hz); 7.31 (d, 1H, J = 7.6 Hz);7.37-7.49 (m, 3H); 7.61 (d, 1H, J = 7.6 Hz); 8.05 (d, 2H, J = 7.3 Hz).2: Obtaining 2-(4-(((2-methoxy-6- Yield: 52%. Appearance: yellow solid.phenylpyridin- ¹H NMR: 1.40 (d, 3H, J = 6.7 Hz); 3.36 (m, 1H);3yl)methyl)amino)phenoxy)propanoic 4.03 (s, 3H); 4.17 (s, 2H); 4.53 (q,1H, J = 6.7 Hz); acid (Protocol SU and PB) 6.48 (d, 2H, J = 8.9 Hz);6.65 (d, 2H, J = 8.9 Hz); 7.37-7.53 (m, 4H); 7.63 (d, 1H, J = 7.6 Hz);8.07 (d, 2H, J = 7.3 Hz). 33 1: Preparation of ethyl 3-(4-(((2- Yield:39%. Appearance: yellow oil. methoxy-6-phenylpyridin-3- ¹H NMR: 1.24 (t,3H, J = 7.3 Hz); 2.58 (t, 2H, yl)methyl)(methyl)- J = 7.3 Hz); 2.87 (t,2H, J = 7.3 Hz); 3.08 (s, 3H); amino)phenyl)propanoate) (Cpd 194.09-4.18 (m, 5H); 4.49 (s, 2H); 6.71 (m, 1H); with Protocol SQ and PA)7.08 (d, 2H, J = 8.5 Hz); 7.29-7.53 (m, 6H); 8.03 (d, 2H, J = 7.0 Hz).2: Obtaining 3-(4-(((2-methoxy-6- Yield: 37%. Appearance: white solidphenylpyridin-3- ¹H NMR: 2.43 (t, 2H, J = 7.3 Hz); 2.67 (t, 2H,yl)methyl)(methyl)amino)phenyl)- J = 7.3 Hz); 3.02 (s, 3H); 4.04 (s,3H); 4.46 (s, propanoic acid (Protocol SU and PA) 2H); 6.59 (d, 2H, J =8.6 Hz); 8.05 (d, 2H, J = 8.6 Hz); 7.32-7.49 (m, 5H); 8.06 (d, 2H, J =7.0 Hz). 37 Obtaining 3-(4-((2-methoxy-6- Yield: 9%. Appearance: whitesolid. phenylpyridin-3- ¹H NMR: 2.41 (t, 2H, J = 7.6 Hz); 2.64 (t, 2H,yl)methylthio)phenyl)propanoic acid J = 7.6 Hz); 4.03 (s, 3H); 4.21 (s,2H); 6.50 (d, 2H, (Ex. 4-16 and 3-(4- J = 8.3 Hz); 6.92 (d, 2H, J = 8.3Hz); 7.36-7.53 (m, mercaptophenyl)propanoic acid with 4H); 7.63 (d, 1H,J = 7.6 Hz); 8.07 (d, 2H, Protocol SQ and PB) J = 7.0 Hz).

Example 8 PPAR Activating Properties of the Compounds According to theInvention

Principle

Activation of PPARs is evaluated in vitro on a line of monkey kidneyfibroblasts (COS-7) by measuring the transcriptional activity ofchimeras consisting of the DNA binding domain of Gal4 transcriptionfactor of yeast and of the ligand binding domain of the various PPARs ofhuman origin (hPPAR). The compounds are tested at doses between 0.01 and100 μM on chimeras Gal4-PPARα, γ, δ and EC₅₀ is determined.

Protocol

a) Cell Culture

The COS-7 cells are from ATCC and are cultivated in DMEM mediumsupplemented with 10% (vol/vol) of fetal calf serum, 1% ofpenicillin/streptomycin (Biochrom, AG), 1% of amino acids (Gibco) and 1%of sodium pyruvate (Gibco). The cells are incubated at 37° C. in a humidatmosphere containing 5% CO₂.

b) Description of the Plasmids Used in Transfection

The plasmids Gal4(RE)_TkpGL3, pGal4-hPPARα, pGal4-hPPARγ, pGal4-hPPARδand pGal4-φ are described in the literature (Raspe E et al., 1999). Theconstructs pGal4-hPPARα, pGal4-hPPARγ and pGal4-hPPARδ were obtained bycloning, into the pGal4-φ vector, DNA fragments amplified by PCRcorresponding to the DEF domains (structural elements of the promoter ofthe PPARs: D=hinge, EF=ligand fixation domain and AF2 fixation site) ofthe human nuclear receptors PPAα, PPARγ and PPARδ.

c) Transfection

The adherent COS-7 cells are transfected with 40 μg of DNA per 225 cm²flask, with a pGal4-hPPAR/Gal4(RE)_TkpGL3 ratio of 1/10, in the presenceof 10% of fetal calf serum. The cells are then detached and seeded inthe absence of serum in 384-well plates (2×10⁴ cells/well) thenincubated for 4 hours at 37° C. The compounds are then diluted in a96-well plate and then transferred to the 384-well plate. Activationwith the test compounds is effected for a further 24 hours at 37° C. inthe presence of 1% of synthetic serum Ultroser™ (Biosepra). These last 2stages are automated by means of a Genesis Freedom 200™ station (Tecan).At the end of the experiment, the cells are lysed and the luciferaseactivity is determined using the Steady-Lite™ HTS (Perkin Elmer)according to the supplier's recommendations.

Results and Conclusion

The inventors thus demonstrated a significant, dose-dependent increaseof luciferase activity in the cells transfected with the pGal4-hPPARplasmids and treated with the compounds according to the invention. Thetest data are summarized in Table 8-1 below, which presents, for eachcompound, the values of maximum activation (TOP %) and the EC₅₀ valuesmeasured for each isoform of PPAR. The values of maximum activation areexpressed in percentages relative to the maximum activations obtainedwith reference agonists: fenofibric acid for PPARα, rosiglitazone forPPARγ and2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxyaceticacid (also called GW501516) for PPARδ.

TABLE 8-1 PPARα PPARγ PPARδ Compound EC50 EC50 EC50 No. TOP % μM TOP %μM TOP % μM 2 48.29 0.143 39.15 12.4 108.56 2.00 3 68.71 0.432 43.643.24 113.83 1.20 4 66.66 1.47 70.47 17.7 114.90 8.67 5 67.52 0.389 57.273.72 70.97 6.17 6 30.27 5.43 17.28 11.8 70.72 0.489 7 28.85 39.6 20.6546.8 96.49 0.550 8 21.94 7.92 13.36 12.2 72.39 2.11 9 33.72 4.50 23.876.09 74.16 0.464 10 53.23 6.06 25.65 10.5 96.74 0.754 11 86.19 0.02254.51 2.45 85.67 3.00 12 78.06 0.195 44.92 2.64 84.16 2.36 13 61.87 1.4324.15 6.93 96.12 3.22 14 58.41 33.3 53.67 24.3 102.80 16.2 15 78.15 3.2446.58 12.3 96.55 1.52 16 78.03 0.510 70.03 5.18 85.15 3.37 17 66.840.009 75.61 0.583 99.60 0.992 18 35.30 10.7 26.08 14.2 97.12 3.97 1967.98 2.37 86.95 1.29 95.12 3.13 20 34.19 14.3 42.98 30.2 87.68 5.26 2170.17 ND 51.48 1.43 99.96 0.276 22 75.94 ND 88.88 1.05 102.03 1.15 2365.27 0.044 75.58 2.84 85.44 0.501 24 76.78 0.371 65.74 4.49 94.08 0.78425 53.90 6.96 38.34 8.29 71.03 6.38 26 66.97 20.9 208.15 44.1 137.9931.1 27 99.78 3.64 98.68 10.6 72.87 41.1 28 55.37 1.74 45.03 11.3 49.1425.2 29 59.30 3.85 57.71 8.43 85.61 10.11 30 38.70 12.1 7.28 ND 1.13 ND31 49.52 2.49 62.35 3.36 86.72 16.3 32 70.40 1.48 66.62 2.51 3.59 22.833 49.93 4.55 64.95 12.4 74.46 10.5 34 67.58 1.42 80.40 2.33 107.790.526 35 26.15 0.647 38.80 6.18 13.16 1.54 36 77.98 0.304 123.27 1.5293.88 0.595 37 65.47 9.95 98.51 9.17 94.71 12.7 38 36.24 10.8 45.37 7.6064.54 6.78 39 52.19 0.175 100.29 1.94 95.28 1.39 40 66.70 0.165 87.250.955 107.35 0.080 41 35.90 7.36 72.14 27.2 107.40 17.0 42 16.53 5.6665.78 4.36 86.55 3.04 43 44.93 1.44 85.61 0.402 77.90 1.51 44 55.480.929 72.21 2.64 80.64 2.38 45 43.20 6.43 79.38 2.39 97.34 3.36 46 60.000.622 69.37 1.94 107.16 0.028 47 58.64 1.90 84.98 1.08 79.17 1.91 4835.92 26.4 58.17 9.57 68.11 16.7 49 51.13 3.62 73.20 4.04 122.96 0.40850 46.76 0.771 63.71 1.92 103.28 0.77 51 50.50 1.29 70.94 2.23 93.121.93 52 34.31 13.7 54.80 2.76 16.07 19.8 53 48.64 5.14 77.95 1.01 9.8610.3 54 34.51 7.97 42.17 4.85 92.14 3.20

The measured activities differ depending on the compound tested and thecompounds according to the invention are also observed to have varyingselectivity with respect to the various isoforms of hPPAR:

-   -   Certain compounds according to the invention are selective for a        subtype of PPAR. This is the case for example for Cpd 11, which        shows high selectivity for hPPARα; the latter activates hPPAR≡        and hPPARδ with EC₅₀ values more than 100 times higher than that        measured on hPPARα. Similarly, Cpd 7 appears to be selective        with respect to hPPARδ.    -   Other compounds according to the invention are simultaneously        activators of two or three subtypes of PPAR. This is the case        notably for Cpd19 and Cpd 1 which activates hPPARα, hPPARγ, and        hPPARδ with comparable EC₅₀. Compound 1 of the invention was        also tested for its PPAR agonist properties. Like Cpd 19, it        displays comparable selectivities for the 3 PPAR isoforms. As        the measurements obtained for compound 1 were carried out        according to a different method and with different equipment,        relative to the other 53 compounds in the examples, the        corresponding results are not presented in Table 8-1 above.

The results obtained show that, in general, the compounds according tothe invention bind and activate the hPPARα, hPPARγ, and/or hPPARδreceptors significantly.

Example 9 Antidiabetic Character of the Compounds According to theInvention

Principle

The aim of this study is to evaluate in vivo the antidiabetic characterof the compounds according to the invention, in the db/db mouse (BergerJ et al., 1996). The antidiabetic effect of the compounds is evaluatedby measuring glycemia and insulinemia after 8 days of treatment. Indiabetic animals (as in humans), administration of glucose leads to asignificant increase in the plasma level of insulin. This inducedhyperinsulinemia causes a lowering of glycemia, which is delayed ininsulin-resistant animals, for example in the db/db mouse. Thecorrective action of the compounds on insulin resistance should notablybe reflected in an improvement of glucose tolerance.

Protocol

a) Treatment of the Animals

Male db/db mice (CERJ—Le Genest St Isle-France) are used for thisexperiment. After acclimation for one week, the mice were weighed andput into groups of 8 animals, selected in such a way that thedistribution of their bodyweight and of their fasting glycemiadetermined for the first time before the experiment are uniform. Thecompound tested was suspended in carboxymethylcellulose (Sigma C4888)and administered by stomach tube, at a rate of once a day for 9 days atthe chosen dose. The animals had free access to water and food (standarddiet) and were housed in ventilated cages with a rhythm of light anddarkness of 12 hours/12 hours at a constant temperature of 20±3° C. Thefood intake and weight gain were recorded throughout the experiment.After administration of the compound for 8 days, a blood sample wastaken by puncture in the retro-orbital sinus of the animals undervolatile anesthesia with isoflurane in order to measure the plasmaconcentrations of glucose and insulin.

After 9 days, the animals were deprived of food for 16 hours beforecarrying out the glucose tolerance test. The latter consists of a singleadministration of glucose after fasting (administered orally at a doseof 1 g/kg). Blood samples were then taken from time to time to study theevolution of plasma glycemia.

b) Measurement of Plasma Insulinemia

Assay of murine insulin is carried out by the Elisa method (InsulinElisa Kit-Crystal Chem. USA). A mouse anti-insulin antibody is fixed ona microplate. The serum to be assayed for insulin is then deposited onthis plate. A guinea pig anti-insulin antibody will recognize theinsulin/mouse monoclonal anti-insulin antibody complex and bind to it.Finally a peroxidase-labeled anti-guinea pig antibody is added, andattaches to the guinea pig anti-insulin antibody. The colorimetricreaction is performed by adding the substrate of the enzyme OPD (OrthoPhenyl Diamine). The intensity of coloration is proportional to theamount of insulin present in the sample.

c) Measurement of Plasma Glycemia

Glucose was determined by enzyme assays (bioMérieux-Lyons-France)according to the suppliers recommendations.

Results and Conclusion

The aim of this study is to evaluate in vivo the antidiabetic characterof a compound according to the invention (Cpd 24) by measuring glycemiaand insulinemia after 8 days of oral treatment with the compoundaccording to the invention. Unexpectedly, the test data obtained showthat Cpd 24, administered at 30 mpk for 8 days, gives an overallimprovement in the glycemic and insulinemic profiles of the diabeticanimals. These results are also reflected in a decrease in the HOMAindex, calculated from these plasma parameters, reflecting animprovement in sensitivity to insulin (FIGS. 8 a, 8 b and 8 c).

In normal and diabetic animals (as in humans), the administration ofglucose leads to a significant increase in the plasma level of insulin.This induced hyperinsulinemia causes a lowering of glycemia, which isdelayed in insulin-resistant animals. The glucose tolerance test alsoshows a marked decrease in insulin resistance in the animals treated for9 days with Cpd 24 (FIGS. 8 d and 8 e).

The compounds according to the invention possess antidiabeticproperties, lowering the plasma levels of glucose and insulin. Thecompounds according to the invention also permit improvement insensitivity to insulin. These results in vivo provide evidence of thetherapeutic potential of the compounds according to the invention withrespect to major pathologies such as type 2 diabetes.

Example 10 Hypolipemic Properties and Stimulating Effect on Synthesis ofHDL-Cholesterol of the Compounds According to the Invention

Principle

The hypolipemic properties of the compounds according to the inventionwere evaluated in vivo by determination of plasma lipids and by analysisof gene expression of targets genes of PPARs in the liver after oraltreatment of a dyslipidemic mouse with the compounds according to theinvention.

The murine model used is the mouse of type ApoE2/E2, a mouse transgenicfor the E2 isoform of human apolipoprotein E (Sullivan P M et al.,1998). In humans, this apolipoprotein, a constituent of low and very lowdensity lipoproteins (LDL-VLDL), occurs in three isoforms E2, E3 and E4.The E2 form has a mutation on an amino acid in position 158, so that theaffinity of this protein for the LDL receptor is greatly reduced.Because of this, clearance of VLDLs is almost zero. This leads toaccumulation of low-density lipoproteins and mixed, so-called type IIIhyperlipidemia (raised cholesterol and triglycerides).

PPARα regulates the expression of genes involved in lipid transport(apolipoproteins such as Apo AI, Apo AII and Apo CIII, membranetransporters such as FAT) or the catabolism of lipids (ACO, CPT-I orCPT-II, enzymes of β-oxidation of fatty acids). Treatment with PPARαactivators is therefore reflected, both in humans and in rodents, in adecrease in levels of circulating triglycerides. Measurement of plasmalipids after treatment with the compounds according to the invention istherefore an indicator of the PPARα agonist character and therefore ofthe hypolipemic action of the compounds according to the invention.

The PPARα agonist properties previously measured in vitro should betranslated at the hepatic level by a change in the level of expressionof the target genes directly under the control of the PPARα receptor:the genes that were studied in these experiments are those coding forACO (a key enzyme in the mechanism of β-oxidation of fatty acids), PDK-4(an enzyme of carbohydrate metabolism) and Apo CIII (apolipoproteininvolved in lipid metabolism). This change in gene expression aftertreatment with the compounds according to the invention is thereforealso an indicator of their hypolipemic character.

Protocol

a) Treatment of the Animals

Apo E2/E2 transgenic mice were kept in a cycle of light and darkness of12 hours/12 hours at a constant temperature of 20±3° C. Afteracclimation for one week, the mice were weighed and put into groups of 6animals selected in such a way that the distribution of their bodyweightand of their plasma lipid values determined first before the experimentare uniform. The compounds tested were suspended incarboxymethylcellulose (Sigma C4888) and administered at the chosen doseby stomach tube, at a rate of once a day for 7 days at the chosen dose.The animals had free access to water and food. At the end of theexperiment, the animals were anesthetized after fasting for 4 hours, ablood sample was taken on anticoagulant (EDTA), then the mice wereweighed and euthanased. The plasma was separated by centrifugation at3000 rev/min for 20 minutes, and the samples were stored at +4° C. forthe biochemical assays. Samples of liver were taken and frozenimmediately in liquid nitrogen and then stored at −80° C. for subsequentanalyses.

b) Measurement of Plasma Lipids

The plasma concentrations of lipids (total cholesterol, HDL-cholesterol,and free fatty acids) were measured by enzyme assays(bioMérieux-Lyons-France) according to the supplier's recommendations.

c) Analysis of Gene Expression by Quantitative RT-PCR

Total RNA was extracted from fragments of liver using the NucleoSpin® 96RNA kit (Macherey Nagel, Hoerdt, France) according to the manufacturer'sinstructions. 1 μg of total RNA (quantified using the Ribogreen RNAquantification kit (Molecular Probes)) was then reverse transcribed tocomplementary DNA by a reaction of 1 hour at 37° C. in a total volume of20 μl containing buffer 1× (Sigma), 1.5 mM of DTT, 0.18 mM of dNTPs(Promega), 200 ng of pdN6 (Amersham), 30U of RNase inhibitor (Sigma) and1 μl of MMLV-RT (Sigma).

The quantitative PCR experiments were performed using the MyiQSingle-Color Real-Time PCR Detection System (Biorad, Marnes-la-Coquette,France) and were carried out using the iQ SYBR Green Supermix kitaccording to the supplier's recommendations, in 96-well plates, on 5 μlof diluted reverse transcription reaction mixtures, with a hybridizationtemperature of 55° C. Specific primer pairs of the genes underinvestigation were used:

PDK4: (SEQ ID NO: 1) sense primer: 5′-TACTCCACTGCTCCAACACCTG-3′ and(SEQ ID NO: 2) antisense primer 5′-GTTCTTCGGTTCCCTGCTTG-3′ ACO:(SEQ ID NO: 3) sense primer: 5′-GAAGCCAGCGTTACGAGGTG-3′ and(SEQ ID NO: 4) antisense primer 5′-TGGAGTTCTTGGGACGGGTG-3′ ApoCIII:(SEQ ID NO: 5) sense primer: 5′-CTCTTGGCTCTCCTGGCATC-3′ and(SEQ ID NO: 6) antisense primer 5′-GCATCCTGGACCGTCTTGGA-3′

The amount of fluorescence emitted is directly proportional to theamount of complementary DNA present at the start of the reaction andamplified during PCR. For each target investigated, a range is preparedby successive dilutions of a pool consisting of a few μl of differentreverse transcription reactions. The relative levels of expression ofeach target are thus determined using the curves of efficacy obtainedwith the scale points.

The levels of expression of the genes of interest were then normalizedrelative to the level of expression of the 36B4 reference gene (whosespecific primers are:

(SEQ ID NO: 11) sense primer: 5'-CATGCTCAACATCTCCCCCTTCTCC-3' and(SEQ ID NO: 12) antisense primer: 5'-GGGAAGGTGTAATCCGTCTCCACAG-3'.

The induction factor, i.e. the ratio of the relative signal (induced bythe compound according to the invention) to the mean of the relativevalues of the control group, was then calculated for each sample. Thehigher this factor, the more the compound has a character of activationof gene expression. The final result is represented as the mean of theinduction values in each experimental group.

Results and Conclusion

a) Measurement of Plasma Lipids

The levels of total cholesterol were decreased after 7 days of treatmentwith compounds 2 and 4 (administered at 10 and 100 mpk; FIG. 9 a) andwith compound 19 administered at 100 mpk (FIG. 10 a). Furthermore,treatment with Cpd 2 or with Cpd 4 led to a dose-dependent increase inplasma level of HDL-cholesterol (FIG. 9 b). Treatment with Cpd 19, at100 mpk, also led to a decrease in plasma level of free fatty acids(FIG. 10 b).

b) Analysis of Gene Expression by Quantitative RT-PCR

Cpd 2 and Cpd 4 induce hepatic overexpression of genes coding for ACOand PDK-4, and significant inhibition of hepatic expression of the genecoding for ApoCIII ((FIGS. 9 c, 9 d, and 9 e).

The compounds according to the invention have hypolipemic properties,lowering the plasma levels of cholesterol and of free fatty acids. Thecompounds according to the invention also have the property ofincreasing the beneficial fraction of HDL-cholesterol. Moreover, thecompounds according to the invention are regulators of expression ofgenes coding for enzymes strongly involved in lipid and carbohydratemetabolism. These results, obtained in vivo, provide evidence of thetherapeutic potential of the compounds according to the invention withrespect to major pathologies such as dyslipidemias.

Example 11 Pparδ Activating Properties of the Compounds According to theInvention From Measurement of the Expression of Target Genes of Pparδ inMyocytes

Principle

The PPARδ agonist properties previously measured in vitro were evaluatedby measuring, in murine myocytes, the expression of genes involved inlipid and carbohydrate metabolism and energy expenditure (PDK4, CPT1b,UCP2). Regulation of expression of these genes, in this cell type, is adirect consequence of the activation of PPARδ by the compounds accordingto the invention. The greater the increase in expression of the genes,the more the compound according to the invention is a stimulator ofmetabolism in muscle cells (Dressel U et al., 2003).

Protocol

a) Differentiation of C2C12 Cells into Myocytes

The C2C12 murine cells (from ECACC) are cultivated in DMEM medium(Gibco; 41965-039) supplemented with 1% L-glutamine (Gibco; 25030), 1%penicillin/streptomycin (VWR; BWSTL0022/100) and 10% decomplementedfetal calf serum (FCS. Gibco; 10270-106).

The cells are seeded in 24-well plates at a density of 50×10³cells/well. At confluence, the medium is replaced with a differentiationmedium (base culture medium supplemented with 2% of horse serum (Gibco;26050-088)) then culture is continued at 37° C. and 5% CO₂ for 7 days inorder to permit differentiation of the myoblasts into myocytes.

b) Treatment

After 6 days of differentiation, the cells are put in a deprivationmedium (base culture medium without serum) for 6 hours. The cells arethen treated with the compounds according to the invention in thedeprivation medium. The compounds according to the invention were testedat doses of 0.1, 1, 10 μM and 0.2, 2 and 20 μM respectively. Thecompounds according to the invention were dissolved in dimethylsulfoxide(DMSO, Sigma; D5879). The cells are treated for 24 hours at 37° C., 5%CO₂. The effects for the compounds tested were compared with the effectof DMSO alone at a concentration of 0.1%.

c) Extraction of RNA, Reverse Transcription and Quantitative PCR

These procedures were performed on the cells essentially as described inExample 10 (point c) of the Protocols.

The following primer pairs specific to the genes investigated were used:

PDK4: (SEQ ID NO: 1) sense primer:  5′-TACTCCACTGCTCCAACACCTG-3′ and(SEQ ID NO: 2) antisense primer 5′-GTTCTTCGGTTCCCTGCTTG-3′ CPT1b:(SEQ ID NO: 7) sense primer: 5′-GGACTGAGACTGTGCGTTCCTG-3′ and(SEQ ID NO: 8) antisense primer 5′-AGTGCTTGGCGGATGTGGTT-3′ UCP2:(SEQ ID NO: 9) sense primer: 5′-GTCGGAGATACCAGAGCACTGTCG-3′ and(SEQ ID NO: 10) antisense primer 5′-CACATCAACAGGGGAGGCGA-3′Results and Conclusion

In murine myocytes in vitro, that the compounds of the invention such asCpd 7 and Cpd 24 possess significant effects of stimulating expressionof genes involved in carbohydrate and lipid metabolism and inthermoregulation, and known to be regulated by agonists of PPARδ, suchas PDK4, CPT1b and UCP2 (FIGS. 11 a, 11 b and 11 c).

The test data presented show that the compounds of the invention have ametabolic action in murine myocytes by activation of PPARδ.

Example 12 PPARγ Activating Properties of the Compounds According to theInvention

Principle

The functional effect of activation of PPARγ is evaluated in vitro on aline of pre-adipocyte cells 3T3-L1 (Thompson G M et al., 2004) bymeasuring the concentration of intracellular triglycerides and theconcentration of adiponectin secreted in the culture medium after 9 daysof treatment with the compounds according to the invention. This effect,similar to that of PPARγ agonist compounds such as thiazolidinediones(Kallen C B and Lazar M A, 1996), demonstrated in vitro the functionalproperties of these compounds.

Protocol

The 3T3-L1 cells (Mus musculus embryo fibroblasts, ATCC; CL-173) arecultivated in DMEM medium (4.5 g/L glucose, Gibco 41965) supplementedwith 10% of fetal calf serum (Gibco; 10270), 1% of L-glutamine (Gibco;25030), 100 units/mL of penicillin+100 μg/mL streptomycin (VWR;BWSTL0022/100) up to confluence (37° C., 5% CO₂). At confluence, thecells were then rinsed with PBS (Phosphate Buffered Saline solution) andthe culture medium was replaced with DMEM 4.5 g/L glucose (10% FCS, 1%L-glutamine, 100 units/mL penicillin and 100 μg/mL streptomycin, 0.25mM) containing a cocktail for initiation of adipocyte differentiation(IBMX (3-isobutyl-1-methylxanthine Sigma; 17018), 0.1 μM dexamethasone(Sigma; D1756) and 0.4 μM of insulin (Sigma; I2643). The cells were alsotreated with the compounds according to the invention (1 μL ofsolubilized compound/mL of medium, 200 μL per well).

After 2 days of incubation, the cells were washed with PBS and thedifferentiation medium was replaced with DMEM 4.5 g/L of glucosesupplemented with 10% FCS, 1% L-glutamine, 100 units/mL penicillin and100 μg/mL streptomycin, 0.4 μM insulin, and the compounds according tothe invention for the purpose of completing cellular differentiation andobtaining adipocytes. The medium was changed every 2 days until totaldifferentiation. After culture for 9 days, the treatment was stopped bywithdrawing the culture medium, which was stored for assaying secretedadiponectin. The cells were then washed twice with PBS and placed inisopropanol for membrane permeabilization. The content of intracellulartriglycerides was evaluated immediately.

Quantification of intracellular triglycerides was performed with the“Triglyceride Enzymatic PAP1000” kit (bioMérieux; 61238) according tothe supplier's recommendations. Secreted adiponectin was measured in theculture medium using the “Mouse Adiponectin/Acrp30 Elisa Kit” kit (R&DSystems; DY1119) according to the supplier's recommendations.

Results and Conclusion

The test data show that Cpd 19, Cpd 24 and Cpd 36 produce dose-dependentstimulation in vitro of accumulation of triglycerides in adipocytes, andsecretion of adiponectin. These results therefore show a PPARγactivating capacity in vitro of the compounds according to theinvention, which is reflected in stimulation of adipogenesis in thecellular model of 3T3-L1 murine pre-adipocytes.

BIBLIOGRAPHY

-   Berger J et al., Endocrinology. 1996, 137(10), 4189-95.-   Blaschke F et al., Arterioscler Thromb Vasc Biol. 2006, 26, 28-40.-   Burger A, Prog Drug Res. 1991, 37, 287-371-   Dressel U et al., Mol Endocr. 2003, 17(12):2477-2493.-   Gervois P et al., Nat Clin Pract Endocrinol Metab, 2007, 3 (2)    145-156.-   Gilde A J et al., J Am Coll Cardiol. 2006, 48(9), A24-A32.-   Gross B et al., Drug Disc Today: Therapeutic Strategies, 2005, 2    (3), 237-243.-   Hansen M K and Connolly T M, Curr Opin Invest Drugs. 2008, 9(3),    247-255.-   Hourton D et al. Biochem J 2001? 354(Pt1), 225-232.-   Kallen C B and Lazar M A, Proc Natl Acad Sci USA. 1996, 93(12),    5793-6.-   Krause B, Curr Opin Invest Drugs. 2008, 9(9), 945-9.-   Lefebvre P et al., J Clin Invest, 2006, 116 (3), 571-580-   Lehrke M and Lazar M A, Cell, 2005, 123 (6), 993-999.-   Lima L M and Barreiro E J, Curr Med Chem. 2005, 12(1), 23-49.-   Peraza M et al., Toxicol. Sci., 2006, 90(2), 269-295.-   Raspe E J Lipid Res, 1999, 40 (11), 2099-110.-   Sullivan P M et al., J Clin Invest. 1998, 102(1), 130-5.-   Thompson G M et al., Anal Biochem. 2004, 330(1), 21-8.

The invention claimed is:
 1. A compound of formula:

in which, G represents: a radical —OR_(a), —SR_(a), or a radical—NR_(a)R_(b), R_(a) being selected from an alkyl radical with 1 to 6carbon atoms or alkenyl radical with 2 to 6 carbon atoms, a ring with 3to 14 atoms, a phenyl radical, a phenylalkyl radical with the alkylmoiety having 1 to 3 carbon atoms; R_(b) being selected from a hydrogenatom, an alkyl radical with 1 to 6 carbon atoms or alkenyl radical with2 to 6 carbon atoms, a ring with 3 to 14 atoms, a phenyl radical, or aphenylalkyl radical with the alkyl moiety having 1 to 3 carbon atoms; orR_(a) and R_(b) can form, together and with the nitrogen atom to whichthey are bound, a heterocycle with 3 to 8 atoms. R₁ and R₂, which may beidentical or different, represent a hydrogen atom or an alkyl radicalwith 1 to 6 carbon atoms or alkenyl radical with 2 to 6 carbon atoms; orR₁ and R₂ can form, together and with the carbon atom to which they arebound, a carbocycle with 3 to 6 carbon atoms; Y₁ represents: a oxygenatom or sulfur atom, or a group —NR—, in which R has the same definitionas R_(b); Y₂ represents: a oxygen atom or sulfur atom, or a radical—CR₅R₆—; with R₅ and R₆, which may be identical or different, selectedfrom a hydrogen atom or halogen atom, an alkyl radical with 1 to 6carbon atoms or an alkenyl or alkynyl radical with 2 to 6 carbon atoms,a ring with 3 to 6 atoms, a phenyl radical, a phenylalkyl radical withthe alkyl moiety having 1 to 3 carbon atoms; X₁, X₂, X₃ representindependently a hydrogen atom or halogen atom, an alkyl radical with 1to 6 carbon atoms or alkenyl radical with 2 to 6 carbon atoms, a group—OR′_(a), —SR′_(a), —NR′_(a)R′_(b), a ring with 5 to 14 atoms, or aphenylalkyl radical with the alkyl moiety having 1 to 3 carbon atoms,with at least one of the groups X₁, X₂ and X₃ different from a hydrogenatom and from a halogen atom; R′_(a) and R′_(b), which may be identicalor different, having the same definitions as R_(a) and R_(b); X₄ and X₅represent independently a hydrogen atom or halogen atom, an alkylradical with 1 to 6 carbon atoms or alkenyl radical with 2 to 6 carbonatoms, a group —OR″_(a), —SR″_(a) or —NR″_(a)R″_(b), a ring with 3 to 14atoms, a phenyl radical, or a phenylalkyl radical with the alkyl moietyhaving 1 to 3 carbon atoms; R″_(a) and R″_(b), which may be identical ordifferent, having the same definitions as R_(a) and R_(b); R₃ and R₄,which may be identical or different, represent a hydrogen atom orhalogen atom, an alkyl radical with 1 to 6 carbon atoms or alkenylradical with 2 to 6 carbon atoms, a ring with 3 to 14 atoms, a phenylradical, or a phenylalkyl radical with the alkyl moiety having 1 to 3carbon atoms; W represents: a carboxyl radical —COOH; or a functionderived from the carboxylic acid function, selected from —COOR′″_(a),—COSR′″_(a), —CONR′″_(a)R′″_(b), —CSNR′″_(a)R′″_(b), —CONH₂; or abioisosteric group of the carboxyl radical, selected from: anacylsulfonamide radical (—CONHSO₂R′″_(a)); a hydrazide radical(—CONHNR′″_(a)R′″_(b)); a radical selected from the thiazolidinedione,oxazolidinedione, tetrazole, oxadiazolone, triazolone, triazole,3-alkyltriazole, or imidazolidinedione rings; R′″_(a) and R″′_(b), whichmay be identical or different, having the same definitions as R_(a) andR_(b).
 2. The compound of claim 1, wherein Y₂ is positioned para or metaof Y₁.
 3. The compound of claim 1, wherein: X₃ denotes a hydrogen atom,and/or X₄ and X₅ denote independently a hydrogen atom, an alkyl radicalhaving 1 to 6 carbon atoms, a group —OR″_(a) or —SR″_(a); R″_(a) beingan alkyl radical having 1 to 6 carbon atoms, and optionally wherein Y₂is positioned para or meta of Y₁.
 4. The compound of claim 1, whereinR₁, R₂, R₃, R₄ denote independently a hydrogen atom or a methyl, ethyl,propyl, butyl, isopropyl or tert-butyl radical.
 5. The compound of claim1, wherein X₃, R₁ and R₂ denote hydrogen atoms.
 6. The compound of claim1, wherein X₁ and/or X₂ denote a ring with 5 to 10 atoms, unsubstitutedor substituted with a —CF₃ group.
 7. The compound of claim 1, wherein Gdenotes a radical —OR_(a) or —SR_(a), with R_(a) selected from alkylradical having 1 to 6 carbon atoms, a cyclohexyl or a phenyl radical; ora radical —NR_(a)R_(b), R_(a) and R_(b) forming together, and with thenitrogen atom to which they are bound, a heterocycle with 3 to 8 atoms.8. The compound of claim 1, wherein G denotes a radical —OR_(a) withR_(a) selected from a methyl, ethyl, propyl, butyl, isopropyl ortert-butyl radical.
 9. The compound of claim 7, wherein: X₂ and X₃denote simultaneously a hydrogen atom; or X₃ and X₁ denotesimultaneously a hydrogen atom.
 10. The compound of claim 1,characterized in that Y₁ denotes an oxygen or sulfur atom, andsimultaneously Y₂ denotes an oxygen atom, a sulfur atom, or a group—CR₅R₆.
 11. The compound of claim 1, characterized in that Y₁ denotes agroup —NR and simultaneously Y₂ denotes an oxygen atom, a sulfur atom ora group —CR₅R₆.
 12. The compound of claim 10, characterized in that X₁denotes an unsubstituted phenyl radical or a phenyl radical substitutedwith a group —CF₃, and/or G denotes a group —OCH₃ or —OC(CH₃)₃.
 13. Thecompound of claim 1, wherein it is selected from: Cpd 1:2-(4-((2-methoxy-6-phenylpyridin-3-yl)methoxy)phenoxy)-2-methyl-propanoicacid Cpd 2:2-(4-((2-methoxy-6-phenylpyridin-3-yl)methoxy)phenoxy)ethanoic acid Cpd3: 2-(4-((2-methoxy-6-phenylpyridin-3-yl)methoxy)phenoxy)propanoic acidCpd 4:2-(4-(((2-methoxy-6-phenylpyridin-3yl)methyl)amino)phenoxy)ethanoic acidCpd 5:2-(4-(((2-methoxy-6-phenylpyridin-3yl)methyl)amino)phenoxy)propanoicacid Cpd 6:2-(4-((2-tert-butyloxy-6-phenylpyridin-3-yl)methoxy)phenoxy)-2-methyl-propanoicacid Cpd 7:2-(4-(((2-tert-butyloxy-6-phenylpyridin-3-yl)methoxy)phenoxy)ethanoicacid Cpd 8: 2-(4-((2-tert-butyloxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)ethanoic acid Cpd 9:2-(4-(((2-tert-butyloxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)-2-methyl-propanoicacid Cpd 10:2-(4-(((2-tert-butyloxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)-propanoicacid Cpd 11:2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenylthio)-2-methyl-propanoicacid Cpd 12:2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)-2-methyl-propanoicacid Cpd 13:2-(3-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)-2-methyl-propanoicacid Cpd 14:2-(3-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)ethanoicacid Cpd 15:2-(4-((2-hexyloxy-6-phenylpyridin-3-yl)methoxy)phenoxy)ethanoic acid Cpd16:2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenylthio)-ethanoicacid Cpd 17:2-(4-((2-hexyloxy-6-phenylpyridin-3-yl)methoxy)phenoxy)-2-methyl-propanoicacid Cpd 18:2-(4-((2-cyclohexyloxy-6-phenylpyridin-3-yl)methoxy)phenoxy)ethanoicacid Cpd 19:3-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenyl)propanoicacid Cpd 20:2-(4-((6-phenyl-2-(piperidin-1-yl)pyridin-3-yl)methoxy)phenoxy)-ethanoicacid Cpd 21:2-(4-((2-methoxy-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methoxy)-phenoxy)-2-methylpropanoicacid Cpd 22:2-(4-(((2-methoxy-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)-phenylthio)-2-methylpropanoicacid Cpd 23:2-(4-(((2-methoxy-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)-phenylthio)ethanoicacid Cpd 24:2-(4-((2-methoxy-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methoxy)-phenoxy)ethanoicacid Cpd 25:2-(4-((2-phenylthio-6-(phenyl)pyridin-3-yl)methoxy)phenoxy)ethanoic acidCpd 26:2-(4-(((2-methoxy-5-phenylpyridin-3-yl)methyl)amino)phenylthio)-ethanoicacid Cpd 27:2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenylthio)-2,2-difluoroethanoicacid Cpd 28:2-(4-(((2-methoxy-5,6-diphenylpyridin-3-yl)methyl)amino)phenylthio)-ethanoicacid Cpd 29:2-(4-(((2-methoxy-5-bromo-6-phenylpyridin-3-yl)methyl)amino)-phenylthio)-ethanoicacid Cpd 30:2-(4-(((2-methoxy-6-furylpyridin-3-yl)methyl)amino)phenylthio)ethanoicacid Cpd 31:3-(4-(((2-methoxy-6-furylpyridin-3-yl)methyl)amino)phenyl)propanoic acidCpd 32:2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenylthio)-2-phenyl-ethanoicacid Cpd 33:3-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)(methyl)amino)phenyl)-propanoicacid Cpd 34:3-(4-(1-((2-methoxy-6-phenylpyridin-3-yl)propyl)amino)phenyl)propanoicacid Cpd 35:2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)-2,6-dimethyl-phenoxy)ethanoicacid Cpd 36:3-(4-(((2-methoxy-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)-phenyl)-propanoicacid Cpd 37:3-(4-((2-methoxy-6-phenylpyridin-3-yl)methylthio)phenyl)propanoic acidCpd 38:3-(4-(((2-(ethylthio)-6-phenylpyridin-3-yl)methyl)amino)phenyl)-propanoicacid Cpd 39:3-(4-(((2-methoxy-6-(parabiphenyl)pyridin-3-yl)methyl)amino)phenyl)-propanoicacid Cpd 40:3-(4-(((2-methoxy-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)-amino)-phenyl)propanoicacid Cpd 41:3-(4-(((2-methoxy-5-phenylpyridin-3-yl)methyl)amino)phenyl)propanoicacid Cpd 42:3-(4-((2(-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenyl)-3-phenyl-propanoicacid Cpd 43:3-(2-methoxy-4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)-phenyl)-propanoicacid Cpd 44:3-(3-methoxy-4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)-phenyl)-propanoicacid Cpd 45:3-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenyl)butanoic acidCpd 46:3-(4-(((2-methoxy-5-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)-amino)phenyl)propanoicacid Cpd 47:3-(4-(((2-methoxy-5-(3-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)-amino)-phenyl)propanoicacid Cpd 48:3-(4-(((2,6-dimethoxy-5-phenylpyridin-3-yl)methyl)amino)phenyl)-propanoicacid Cpd 49:3-(4-(((5-(4-chlorophenyl)-2-methoxypyridin-3-yl)methyl)amino)phenyl)-propanoicacid Cpd 50:3-(4-(((2-methoxy-5-(naphthalen-2-yl)pyridin-3-yl)methyl)amino)phenyl)-propanoicacid Cpd 51:3-(4-(((2-ethoxy-6-phenylpyridin-3-yl)methyl)amino)phenyl)propanoic acidCpd 52: 3-(4-((2-methoxy-5-phenylpyridin-3-yl)methoxy)phenyl)hex-4-ynoicacid Cpd 53:3-(4-((2-methoxy-6-phenylpyridin-3-yl)methoxy)phenyl)hex-4-ynoic acidCpd 54:3-(4-(((2-isopropyloxy-6-phenylpyridin-3-yl)methyl)amino)phenyl)-propanoicacid.
 14. A pharmaceutical composition comprising, in a pharmaceuticallyacceptable carrier, at least one compound as defined in claim 1,optionally in combination with one or more other therapeutic and/orcosmetic active substances.
 15. The pharmaceutical composition of claim14 for the therapeutic, curative and/or prophylactic treatment ofdiabetes, dyslipidemias, insulin resistance, pathologies associated withmetabolic syndrome, atherosclerosis, cardiovascular diseases, obesity,hypertension and/or inflammatory diseases.
 16. A method of therapeuticand/or prophylactic treatment of diabetes, dyslipidemias, insulinresistance, pathologies associated with metabolic syndrome,atherosclerosis, and cardiovascular diseases, obesity, hypertensionand/or inflammatory diseases, comprising the administration, to a humansubject, of an effective amount of a compound as defined in claim
 1. 17.The compound of claim 12, characterized in that said group —CF₃ is inpara of the pyridinyl radical.